MaltSci 麦伴科研

Appearance

Popular Reports / hematology

This report is written by MaltSci based on the latest literature and research findings

How does leukemia develop and progress? ​

Abstract ​

Leukemia encompasses a diverse and complex group of hematological malignancies characterized by the uncontrolled proliferation of abnormal white blood cells. Its pathogenesis is influenced by a multitude of genetic, epigenetic, and environmental factors, making it imperative to understand these underlying mechanisms for improved diagnostic and therapeutic strategies. This review systematically categorizes the types of leukemia, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML), highlighting their unique biological characteristics and the role of genetic mutations in their development. Genetic alterations such as chromosomal translocations and mutations significantly impact disease progression and therapeutic responses. Epigenetic modifications further complicate the landscape of leukemia by affecting gene expression and maintaining leukemic stem cells (LSCs), which are crucial for disease initiation and relapse. Environmental factors, including chemical exposures and lifestyle choices, also contribute to the risk of developing leukemia, necessitating a comprehensive approach to prevention and intervention. The bone marrow microenvironment is a critical player in leukemia pathogenesis, influencing tumor growth and resistance to therapy. Current and emerging therapeutic strategies are increasingly focused on personalized medicine, aiming to tailor treatments based on individual genetic and epigenetic profiles. By synthesizing recent research findings, this review provides an in-depth overview of the mechanisms driving leukemia development and progression, offering valuable insights for researchers and clinicians alike.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Types of Leukemia
    • 2.1 Acute Lymphoblastic Leukemia (ALL)
    • 2.2 Acute Myeloid Leukemia (AML)
    • 2.3 Chronic Lymphocytic Leukemia (CLL)
    • 2.4 Chronic Myeloid Leukemia (CML)
  • 3 Genetic and Epigenetic Factors
    • 3.1 Genetic Mutations and Chromosomal Abnormalities
    • 3.2 Role of Epigenetics in Leukemia
    • 3.3 Impact of Inherited Genetic Predispositions
  • 4 Environmental and Lifestyle Factors
    • 4.1 Chemical Exposures
    • 4.2 Radiation and Viral Infections
    • 4.3 Lifestyle Factors and Their Influence
  • 5 Bone Marrow Microenvironment and Immune System
    • 5.1 Role of the Bone Marrow Niche
    • 5.2 Immune Evasion Mechanisms
    • 5.3 Interaction Between Leukemic Cells and the Immune System
  • 6 Current and Emerging Therapeutic Strategies
    • 6.1 Conventional Chemotherapy
    • 6.2 Targeted Therapies and Immunotherapies
    • 6.3 Advances in Personalized Medicine
  • 7 Summary

1 Introduction ​

Leukemia represents a complex and heterogeneous group of hematological malignancies characterized by the uncontrolled proliferation of abnormal white blood cells. This group of diseases can arise from various hematopoietic stem cell lineages, leading to distinct clinical manifestations and outcomes. The pathogenesis of leukemia is multifactorial, involving a combination of genetic, epigenetic, and environmental factors that collectively contribute to its development and progression. As our understanding of these underlying mechanisms improves, it becomes increasingly evident that a comprehensive approach is essential for enhancing diagnostic accuracy, therapeutic strategies, and ultimately, patient outcomes.

The significance of understanding leukemia lies not only in its high incidence and prevalence but also in the profound impact it has on patients and healthcare systems worldwide. Leukemia accounts for a substantial proportion of cancer-related morbidity and mortality, particularly among children and young adults. The complexities associated with its etiology and the intricate interplay between genetic mutations, epigenetic alterations, and environmental influences underscore the need for continued research in this field. By elucidating the mechanisms of leukemia development and progression, we can identify potential therapeutic targets and develop more effective, personalized treatment strategies.

Current research has revealed critical insights into the genetic and epigenetic landscape of leukemia. Genetic mutations, such as those affecting the BCR-ABL1 fusion gene in chronic myeloid leukemia (CML) and mutations in the CSF3R gene associated with chronic neutrophilic leukemia, play pivotal roles in the pathogenesis of these diseases [1][2]. Furthermore, epigenetic modifications have been implicated in the regulation of gene expression and the maintenance of leukemic stem cells (LSCs), which are crucial for disease initiation and relapse [3][4]. Understanding these genetic and epigenetic factors provides a foundation for the development of targeted therapies and innovative treatment approaches.

Environmental and lifestyle factors also significantly contribute to the risk of developing leukemia. Exposure to certain chemicals, such as benzene, and ionizing radiation have been well-documented as risk factors [5]. Moreover, lifestyle factors, including diet and physical activity, may influence the incidence and progression of leukemia [6]. This multifactorial etiology necessitates a holistic approach to prevention and intervention, taking into account both genetic predispositions and environmental exposures.

The bone marrow microenvironment plays a crucial role in the pathogenesis of leukemia, providing a supportive niche for leukemic cells. Interactions between leukemic cells and the bone marrow stroma can promote tumor growth and resistance to therapy [7]. Understanding these interactions is vital for developing strategies that can disrupt the supportive microenvironment, thereby enhancing the efficacy of existing treatments.

In this review, we will systematically explore the various aspects of leukemia development and progression. The discussion will be organized as follows: we will begin by categorizing the different types of leukemia, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML), highlighting their unique biological characteristics. Next, we will delve into the genetic and epigenetic factors that contribute to leukemogenesis, followed by an examination of environmental and lifestyle influences. Subsequently, we will discuss the role of the bone marrow microenvironment and immune system interactions in leukemia progression. Finally, we will review current and emerging therapeutic strategies, emphasizing the importance of personalized medicine in managing leukemia. By synthesizing recent research findings, this review aims to provide a comprehensive overview of how leukemia develops and progresses, serving as a valuable resource for researchers and clinicians in the field.

2 Types of Leukemia ​

2.1 Acute Lymphoblastic Leukemia (ALL) ​

Acute lymphoblastic leukemia (ALL) is primarily a hematological malignancy that predominantly affects children, characterized by the clonal expansion of immature lymphoid cells, specifically B and T cell precursors. The development and progression of ALL are driven by a series of genetic insults that disrupt normal cell differentiation and promote aberrant proliferation and survival of these precursors.

The pathogenesis of ALL is significantly influenced by recurrent genetic alterations, including chromosomal translocations, aneuploidies, and gene-specific mutations. These genetic aberrations result in the formation of distinct molecular subgroups of B-ALL and T-ALL, each associated with varying clinical outcomes and responses to therapy (Teitell & Pandolfi, 2009) [8]. For instance, approximately 60% of T-ALL cases exhibit aberrant expression of transcription factors such as TAL1 and LYL1, which are crucial regulators of T cell growth and differentiation. The dysregulation of these factors is a key event in the leukemogenesis of T-ALL (Parriott & Kee, 2022) [9].

The microenvironment of leukemia, particularly the bone marrow niche, also plays a critical role in the disease's progression. Factors within this microenvironment, including chemokines and stromal cells, have been shown to contribute to the pathogenesis of ALL and can mediate chemoresistance. For example, chemokine axes such as CXCL12/CXCR4 and CCL25/CCR9 have been implicated in influencing leukemia cell behavior, including proliferation and drug resistance (Hong et al., 2021) [10]. The interactions between leukemic cells and their microenvironment are pivotal in determining treatment outcomes and disease relapse.

Furthermore, recent advancements in genomic technologies, particularly next-generation sequencing (NGS), have enhanced our understanding of the genetic heterogeneity of ALL. NGS has facilitated the identification of novel genetic variants and molecular subtypes, allowing for better patient stratification and personalized therapeutic approaches (Ramírez Maldonado et al., 2024) [11].

In terms of treatment, ALL management has evolved significantly over the years. While pediatric patients have shown improved survival rates due to intensive multi-agent chemotherapy regimens, adult patients often experience poorer outcomes due to a higher likelihood of treatment resistance and the complexity of their disease (Crazzolara & Bendall, 2009) [12]. Emerging therapies, including targeted agents and immunotherapies, are currently being explored to address these challenges and improve treatment efficacy (Pagliaro et al., 2024) [13].

In summary, the development and progression of acute lymphoblastic leukemia involve a complex interplay of genetic alterations, microenvironmental factors, and treatment responses. Understanding these mechanisms is crucial for the advancement of therapeutic strategies and improving patient outcomes.

2.2 Acute Myeloid Leukemia (AML) ​

Acute myeloid leukemia (AML) is a complex and heterogeneous hematological malignancy characterized by the clonal proliferation of myeloid stem and progenitor cells. The development and progression of AML are driven by a series of genetic and epigenetic alterations that disrupt normal hematopoietic differentiation and lead to uncontrolled cell growth.

The pathogenesis of AML typically involves multiple molecular events that confer unlimited self-renewal potential to primitive hematopoietic progenitors, causing defective differentiation. Various genetic aberrations, including gene mutations and chromosomal abnormalities, play a crucial role in the transformation of normal hematopoietic stem cells into leukemic cells. These aberrations often lead to the generation of dysfunctional molecules that disrupt regulatory mechanisms governing survival, proliferation, and differentiation in normal stem and progenitor cells [14].

Genetic abnormalities in AML can be categorized into two main types: cytogenetic aberrations and small-scale genetic mutations, such as single-nucleotide variations and insertion/deletion mutations. Cytogenetic changes are particularly prominent in cases of AML with abnormal karyotypes, while gene mutations are more prevalent in cytogenetically normal AML. The evolution of AML is marked by clonal diversity, where preleukemic clones undergo transformation into overt leukemia, followed by the expansion and recurrence of malignant clones. This clonal evolution is often associated with increasing genetic diversification, where more evolved subclones exhibit a proliferative advantage or more aggressive behavior compared to their ancestors [15].

The bone marrow microenvironment significantly influences the progression of AML. It alters the behavior of hematopoietic cells and contributes to sustained cytopenia and immunodeficiency. The interaction between leukemic cells and the microenvironment can also impact the immune response, particularly affecting T lymphocytes, which play a vital role in orchestrating adaptive immunity [16]. Moreover, chronic immune stimulation and aberrant cytokine signaling have been implicated in the initiation and progression of AML, highlighting potential therapeutic targets [17].

Epigenetic dysregulation has emerged as a critical driver of leukemogenesis in AML. Abnormal DNA methylation patterns, dysregulated histone modifications, and disrupted chromatin architecture are commonly observed in leukemic cells. These epigenetic changes can silence key differentiation genes and sustain self-renewal pathways, reinforcing the developmental arrest and hyper-proliferation characteristic of AML [18].

Furthermore, mitochondrial metabolism plays a significant role in the progression of AML. The altered energy dependency of leukemic cells, originally proposed by Warburg, highlights the importance of mitochondrial function in cell proliferation and differentiation. Studies indicate that targeting mitochondrial pathways may provide new therapeutic avenues for managing relapsed or refractory AML [19].

In summary, the development and progression of AML are the result of a complex interplay between genetic mutations, epigenetic alterations, and environmental factors within the bone marrow niche. Understanding these mechanisms is essential for the development of targeted therapies aimed at improving outcomes for AML patients.

2.3 Chronic Lymphocytic Leukemia (CLL) ​

Chronic lymphocytic leukemia (CLL) is a hematological malignancy characterized by the accumulation of functionally deficient B lymphocytes in the blood, bone marrow, and lymphatic tissues. The pathogenesis of CLL is complex and involves multiple factors including genetic alterations, immune evasion, and interactions with the tumor microenvironment (TME).

The disease primarily arises from defects in apoptosis, leading to the accumulation of clonal B-lymphocytes that are often arrested in the early phases of the cell cycle (G0, G1) [20]. CLL is associated with various genetic lesions that can influence disease progression and treatment response [21]. For instance, the immunoglobulin heavy-chain variable region gene (IGHV) mutational status and other genomic changes play critical roles in determining the clinical course of the disease [22].

A significant feature of CLL is the high levels of extracellular adenosine (ADO) within the TME, resulting from the activity of ecto-enzymes like CD39 and CD73. ADO signaling has multiple effects, including modulation of cell cycle control, immunoregulation, and angiogenesis, which collectively contribute to the pathogenesis of CLL [23]. The tumor microenvironment, composed of various accessory cells, also provides supportive signals that promote the survival and proliferation of CLL cells. This includes direct interactions through adhesion molecules and the release of soluble factors [24].

Moreover, the biology of CLL is intricately linked to its microenvironment. For instance, the interactions between CLL cells and stromal cells in lymphoid tissues can lead to the activation of survival pathways, enhancing the resistance of leukemic cells to apoptosis [25]. The CLL cells can manipulate the surrounding normal cells to create a supportive niche that favors their growth [24].

Research has also highlighted the role of exosomes—small extracellular vesicles released by CLL cells—in tumor progression and survival. These exosomes carry various biologically active molecules, including microRNAs and proteins, that can influence the behavior of recipient cells and contribute to the malignant process [26].

Clinical outcomes in CLL are heterogeneous, with some patients experiencing indolent disease while others progress rapidly. Factors influencing this variability include the presence of autoimmune complications, which are common in CLL patients and correlate with poor prognosis [27]. Furthermore, the understanding of the redox state of CLL cells, particularly low catalase expression leading to redox hypersensitivity, has been linked to slower disease progression [28].

In summary, the development and progression of CLL involve a multifaceted interplay between genetic factors, immune evasion mechanisms, and the tumor microenvironment, underscoring the complexity of this disease and the need for targeted therapeutic strategies.

2.4 Chronic Myeloid Leukemia (CML) ​

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the BCR-ABL1 fusion gene, which results from a reciprocal translocation between chromosomes 9 and 22, specifically t(9;22)(q34;q11.2). This genetic abnormality leads to the production of a constitutively active tyrosine kinase, the BCR-ABL fusion protein, which plays a critical role in the pathogenesis of CML by promoting uncontrolled proliferation of myeloid lineage cells and contributing to their survival [29].

The progression of CML is typically divided into two phases: the chronic phase (CP) and the blast phase (BP). In the chronic phase, the disease is often asymptomatic, but as it advances, some patients may experience progression to the blast phase, which is characterized by a more aggressive clinical course and poor prognosis. The transition from CP to BP is multifactorial and involves various mechanisms, including genetic mutations and epigenetic changes. An increase in BCR-ABL1 transcript levels can lead to secondary chromosomal defects and genetic abnormalities that contribute to the evolution of the disease [1].

Research has identified several key factors contributing to the development and progression of CML. One significant aspect is the role of aberrant DNA methylation, which has been shown to be involved in the disease evolution and resistance to tyrosine kinase inhibitors (TKIs). For instance, studies indicate that DNA methylation changes can be triggered by oncogenic lesions, acting as precipitating events in leukemia progression [30]. Additionally, persistent leukemic stem cells (LSCs), which share characteristics with normal hematopoietic stem cells but exhibit differences in functionality, are recognized as crucial for disease maintenance and relapse [31].

Furthermore, CML is associated with various molecular abnormalities, including mutations in tumor suppressor genes like p53, which can lead to increased resistance to apoptosis and contribute to the poor prognosis seen in patients transitioning to the blast phase [32]. The interaction between leukemic cells and their bone marrow microenvironment also plays a vital role in disease progression, influencing both the biology of CML cells and their response to therapy [33].

In summary, the development and progression of CML involve a complex interplay of genetic and epigenetic factors, with the BCR-ABL fusion gene as a central driver. The disease progresses from a relatively indolent chronic phase to a more aggressive blast phase, influenced by genetic mutations, the presence of leukemic stem cells, and alterations in the bone marrow microenvironment. Understanding these mechanisms is crucial for developing effective therapeutic strategies to combat CML and improve patient outcomes [34].

3 Genetic and Epigenetic Factors ​

3.1 Genetic Mutations and Chromosomal Abnormalities ​

Leukemia develops as a result of complex interactions between genetic mutations and epigenetic alterations. It is characterized as a monoclonal disease arising from hematopoietic stem and progenitor cells, and its pathogenesis involves multiple independent genetic and epigenetic events (Irons and Stillman 1996).

Genetic mutations play a significant role in the initiation and progression of leukemia. These mutations can be pre-existing or acquired, often resulting in chromosomal abnormalities that are detectable in leukemic cells. For instance, somatically acquired genetic changes, including specific translocations and mutations of cellular oncogenes, are common in leukemia and contribute to the disturbance of the balance between cellular proliferation and differentiation, a crucial step in leukemogenesis (Hagemeijer 1992).

In addition to genetic factors, epigenetic modifications significantly influence leukemia development. These alterations include DNA methylation, histone modifications, and the regulation of non-coding RNAs, which collectively impact gene expression without changing the underlying DNA sequence. Epigenetic changes, such as DNA hypermethylation and aberrant histone modifications, are frequently observed in various types of leukemia, including acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) (Fathi et al. 2021; Zhang et al. 2024).

For example, in acute lymphoblastic leukemia, the modification patterns of DNA methylation and histones are considered characteristic features, driving the malignant phenotype by affecting processes such as proliferation, differentiation, and apoptosis of leukemic cells (Ranjbar et al. 2019). Furthermore, the dysregulation of microRNAs, which are small non-coding RNAs that play a crucial role in gene expression, has been implicated in the pathogenesis of ALL, suggesting that both genetic and epigenetic factors must be considered to understand the disease fully (Memari et al. 2018).

The progression of leukemia is often linked to the accumulation of genetic and epigenetic changes over time, leading to a more aggressive disease phenotype. For instance, chronic lymphocytic leukemia exhibits a heterogeneous nature where alterations in gene expression profiles, regulated by epigenetic mechanisms, play a vital role in its development and progression (Zhang et al. 2024).

In summary, leukemia's development and progression are driven by a combination of genetic mutations, including chromosomal abnormalities and oncogene modifications, alongside significant epigenetic alterations that affect gene expression and cellular behavior. Understanding these intricate interactions is essential for developing targeted therapies and improving patient outcomes.

3.2 Role of Epigenetics in Leukemia ​

Leukemia is characterized as a group of malignant clonal hematopoietic stem cell disorders where both genetic and epigenetic factors play crucial roles in its development and progression. The pathogenesis of leukemia involves a complex interplay of various epigenetic alterations, which significantly influence gene expression and cellular function.

Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNA dysregulation, are critical in the progression of leukemia. For instance, DNA methylation is one of the most common epigenetic changes observed in leukemia. In particular, DNA methyltransferase inhibitors, such as azidothymidine, can reverse aberrant DNA methylation patterns, thereby reactivating silenced oncogenes, which inhibits the proliferation of leukemia cells and induces apoptosis [35]. Additionally, histone acetylase inhibitors and histone methylase inhibitors can regulate histone acetylation and methylation, further impacting gene expression and the cell cycle. These therapeutic agents aim to inhibit malignant proliferation and promote differentiation or apoptosis in leukemia cells by altering their epigenetic state [35].

The role of non-coding RNAs, particularly microRNAs (miRNAs), is also significant in the epigenetic regulation of leukemia. MiRNAs can modulate the expression of various genes involved in processes such as proliferation, differentiation, and apoptosis of leukemia cells [36]. The dysregulation of miRNAs and other epigenetic factors contributes to the initiation and progression of leukemia, making them promising therapeutic targets [37].

Moreover, the understanding of epigenetic mechanisms has led to the recognition that leukemia development can be driven by a malignant epigenetic reprogramming of leukemia-initiating cells. This reprogramming is not exclusive to hematopoietic tumors but is a broader phenomenon observed in various types of cancers [38]. The interaction between oncogenes and epigenetic modifications plays a pivotal role in establishing a pathological tumoral identity, which may remain latent until triggered by environmental or endogenous factors [38].

In summary, the development and progression of leukemia are intricately linked to both genetic and epigenetic factors. Epigenetic alterations, including DNA methylation, histone modifications, and the regulation by non-coding RNAs, are central to the disease's pathogenesis. As research continues to elucidate these mechanisms, epigenetic therapy emerges as a promising avenue for treating leukemia, providing novel strategies to combat this complex disease [35][37][39].

3.3 Impact of Inherited Genetic Predispositions ​

Leukemia development and progression are influenced by a complex interplay of genetic and epigenetic factors, including inherited genetic predispositions. While the majority of leukemia cases occur without identifiable predisposing factors, certain germline mutations significantly elevate the risk of developing hematopoietic malignancies, particularly in childhood. These predispositions can be categorized into several groups: those leading to bone marrow failure, mutations in tumor suppressor genes, defects in DNA repair mechanisms, immunodeficiencies, and congenital syndromes associated with transient myeloid disorders [40].

In particular, conditions such as Down syndrome have been associated with an increased incidence of acute myeloid leukemia (AML) and other hematological malignancies. The underlying mechanisms often involve genetic instability, RAS pathway dysfunction, and other molecular abnormalities that contribute to the leukemogenic process [41]. Moreover, advances in high-throughput genotyping technologies have enabled the identification of new genetic variations that predispose individuals to leukemia, enhancing our understanding of the hereditary factors involved in leukemogenesis [41].

Epigenetic modifications also play a critical role in leukemia. These modifications, including DNA methylation, histone modifications, and dysregulation of non-coding RNAs, affect gene expression and cellular functions, thus driving leukemia development [35]. For instance, in acute lymphoblastic leukemia (ALL), epigenetic alterations such as DNA hypermethylation and histone modification are considered significant contributors to the disease's progression [39]. Targeting these epigenetic abnormalities has emerged as a promising therapeutic strategy, as reversing aberrant DNA methylation patterns can reactivate silenced oncogenes and inhibit the proliferation of leukemia cells [35].

The interaction between genetic predispositions and environmental factors further complicates the etiology of leukemia. For example, specific environmental risk factors, such as infections or exposure to chemicals, may trigger the transformation of preleukemic cells into fully malignant leukemia cells in genetically susceptible individuals [42]. The dual-hit hypothesis suggests that an initial genetic insult, often acquired before birth, must be followed by a second hit, typically influenced by postnatal environmental exposures, to result in leukemia [42].

Overall, the progression of leukemia is a multifaceted process involving both inherited genetic predispositions and epigenetic modifications. Understanding these factors is crucial for developing targeted therapies and preventive strategies, particularly for individuals with known genetic susceptibilities. Future research is expected to continue unraveling the complexities of these interactions, providing deeper insights into the mechanisms of leukemia development and progression [43] [35].

4 Environmental and Lifestyle Factors ​

4.1 Chemical Exposures ​

Leukemia, a complex group of malignancies affecting the blood and bone marrow, has multifactorial origins that encompass both genetic and environmental factors. Among the environmental factors, chemical exposures have been identified as significant contributors to the development and progression of leukemia.

Chemical agents play a crucial role in the etiology of lymphohematopoietic cancers, including leukemia. According to Eastmond et al. (2014), more than 25% of the human carcinogens identified by the International Agency for Research on Cancer are linked to the induction of leukemias or lymphomas. Specific agents such as benzene, a well-documented carcinogen, have been associated with acute myeloid leukemia (AML) in humans. The mechanisms by which benzene induces leukemia are primarily through DNA-damaging effects, resulting in gene or chromosomal mutations [44]. Furthermore, the review emphasizes that while certain chemical agents predominantly induce acute myeloid leukemia, others may be linked to lymphoid neoplasms through alterations in immune response [44].

In a more focused investigation of childhood leukemia, Jin et al. (2016) noted that environmental risk factors such as ionizing radiation and benzene exposure are significant contributors to the incidence of leukemia in children. The review highlighted that while these two factors are well-established, there is a need for further exploration into other environmental exposures, including pesticides and parental substance use [45].

Moreover, the study by Shahbaz et al. (2025) highlighted the influence of lifestyle and demographic factors on leukemia risk in a Pakistani cohort. This research found associations between leukemia and factors such as passive smoking, rural residence, and poor nutrition. The use of advanced machine learning techniques allowed for the identification of these lifestyle factors, suggesting that lifestyle adaptations could be vital for risk mitigation [46].

In addition to benzene, other environmental agents have been linked to leukemia development. For instance, formaldehyde has been under scrutiny for its potential association with acute myeloid leukemia, although the evidence remains controversial [44]. Furthermore, exposure to gasoline and its byproducts has been implicated in elevated risks of childhood leukemia, with significant associations noted with parental occupational exposures to benzene and related chemicals [47].

The intricate interplay of genetic predispositions and environmental exposures, particularly chemical agents, underscores the complexity of leukemia's development. The research indicates that while progress has been made in understanding the role of chemical exposures in leukemia, significant gaps remain. Continued investigation into the mechanisms by which these environmental factors induce leukemia is essential for effective risk assessment and the development of preventive strategies [44][45][46].

4.2 Radiation and Viral Infections ​

Leukemia development and progression are influenced by a complex interplay of genetic and environmental factors, with particular emphasis on radiation exposure and viral infections. Acute leukemias, which are among the most prevalent malignant disorders, have their etiology largely shrouded in uncertainty despite advances in treatment. Various genetic mutations and environmental exposures during preconception, pregnancy, and throughout life have been implicated in the onset of these diseases. Notably, exposure to ionizing radiation is a recognized significant environmental risk factor for leukemia, particularly in children [45].

In childhood leukemia (CL), research highlights the multifactorial nature of its causation, with both genetic predispositions and environmental exposures playing crucial roles. The German Federal Office for Radiation Protection has facilitated international workshops to explore these factors, emphasizing the need for a deeper understanding of the interactions between genetic and environmental influences [48]. The role of infections as environmental risk factors has gained particular attention, especially concerning acute lymphoblastic leukemia (ALL). For instance, certain mouse models, such as Pax5+/- and Sca1-ETV6-RUNX1, demonstrate that leukemia development is contingent upon exposure to common infections, suggesting that gene-environment interactions significantly impact the risk of developing CL [48].

Furthermore, specific viral infections have been linked to leukemogenesis. For example, the presence of a mycovirus-infected Aspergillus flavus has been suggested as a potential contributor to the development of leukemia, underscoring the importance of environmental pathogens in the disease's etiology [43]. The complexities surrounding these interactions indicate that while certain environmental exposures, such as radiation and viral infections, are critical, the precise timing, sequence, and mechanisms of their influence on leukemia development remain subjects of ongoing investigation [43].

Overall, the interplay between environmental factors like radiation and infections, along with genetic predispositions, shapes the risk and progression of leukemia. Understanding these relationships is essential for developing effective prevention and treatment strategies for this malignancy. Further research is warranted to elucidate the mechanisms involved and to identify additional environmental factors that may contribute to leukemia pathogenesis.

4.3 Lifestyle Factors and Their Influence ​

Leukemia development and progression are influenced by a multifactorial interplay of genetic and environmental factors, with lifestyle factors playing a significant role. While the precise etiology of leukemia remains largely unknown, several lifestyle-related elements have been identified that may contribute to the disease.

Firstly, exposure to various chemicals is a critical environmental factor associated with leukemia. Individuals who are exposed to certain chemicals in their occupational settings or through lifestyle choices may have an increased risk of developing leukemia. For instance, the use of pesticides, solvents, and other hazardous substances has been linked to the incidence of leukemia, particularly in adults. This suggests that lifestyle choices, including occupational hazards and the use of certain household products, can significantly influence leukemia risk.

Secondly, the role of infections as environmental risk factors has been highlighted, particularly in childhood leukemia. Research indicates that infections can interact with genetic predispositions to promote leukemogenesis. For example, the findings from recent studies indicate that specific infections may play a role in the development of acute lymphoblastic leukemia, the most common form of leukemia in children. The interplay between infections and genetic factors emphasizes the importance of considering lifestyle and environmental exposures in understanding leukemia risk [48].

Moreover, the concept of gene-environment interactions has gained traction in leukemia research. Individuals with a genetic predisposition to leukemia may experience heightened risk when exposed to certain environmental factors, such as infections or chemicals. This interaction can lead to the acquisition of genetic mutations and epigenetic changes that drive the progression of the disease [43].

Additionally, lifestyle factors such as smoking and dietary habits have been suggested to influence the risk of leukemia. Smoking is known to introduce various carcinogens into the body, which may contribute to the development of hematological malignancies. Furthermore, a diet low in essential nutrients may compromise the immune system, potentially increasing susceptibility to infections that could trigger leukemia [4].

In summary, the development and progression of leukemia are complex processes influenced by a combination of genetic predispositions and environmental factors, including lifestyle choices. Continued research is necessary to elucidate the precise mechanisms by which these factors interact and contribute to leukemia, with an emphasis on identifying modifiable lifestyle factors that could potentially reduce risk.

5 Bone Marrow Microenvironment and Immune System ​

5.1 Role of the Bone Marrow Niche ​

Leukemia development and progression are significantly influenced by the bone marrow microenvironment, which serves as a complex and dynamic niche essential for hematopoiesis. This microenvironment comprises various cellular and acellular components, including stromal cells, immune cells, and extracellular matrix elements, which interact with hematopoietic stem cells (HSCs) and their progenitors. The interplay between leukemic cells and the bone marrow niche not only supports the survival and proliferation of leukemic cells but also contributes to therapeutic resistance and disease relapse.

Leukemic cells disrupt the normal functioning of the bone marrow microenvironment, creating a leukemia-supportive niche that favors their growth. For instance, in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), leukemic cells can modify the tumor immune microenvironment (TIME), promoting immunological evasion and enhancing their own survival [49]. This alteration allows leukemic cells to escape from immune surveillance mechanisms, leading to disease progression.

The bone marrow microenvironment plays a crucial role in mediating drug resistance in leukemia. Studies have shown that leukemic cells can manipulate the niche by secreting factors that alter the behavior of mesenchymal stem cells (MSCs) and other stromal components. For example, leukemia-associated MSCs exhibit reduced self-renewal capacity and significant changes in molecular signatures, which can support leukemic cell survival and inhibit normal hematopoiesis [50]. Additionally, the interactions between leukemic cells and the bone marrow stroma can generate anti-apoptotic signals, further contributing to treatment resistance [7].

Moreover, the bone marrow microenvironment is enriched with signaling pathways that leukemic cells exploit to promote their survival. For instance, the CXCR4-CXCL12 axis is involved in the retention of leukemic cells within the bone marrow, facilitating their persistence and resistance to therapies [7]. The presence of proangiogenic factors, such as vascular endothelial growth factor (VEGF), also enhances leukemogenesis by promoting angiogenesis, which is crucial for tumor growth and survival [51].

Recent advancements in understanding the bone marrow niche have highlighted its potential as a therapeutic target. By disrupting the interactions between leukemic cells and their microenvironment, novel strategies may enhance the efficacy of existing treatments and overcome the protective influence of the bone marrow [52]. For instance, targeting the adipocyte-leukemia axis could sensitize leukemic cells to chemotherapy and improve patient outcomes [52].

In summary, leukemia progression is intricately linked to the bone marrow microenvironment, which not only supports leukemic cell survival and proliferation but also plays a pivotal role in drug resistance and disease relapse. A deeper understanding of these interactions may lead to innovative therapeutic approaches aimed at targeting the leukemic niche to improve treatment efficacy and patient prognosis.

5.2 Immune Evasion Mechanisms ​

Leukemia development and progression are significantly influenced by the bone marrow microenvironment (BMME) and the immune system's interactions within it. The BMME serves as a complex ecosystem that not only supports normal hematopoiesis but also facilitates the survival and proliferation of leukemic cells. This microenvironment is characterized by a dynamic network of cytokines, growth factors, and stromal cells that contribute to the pathological processes observed in leukemia.

In the context of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), leukemic cells can disrupt the physiological hematopoietic niche in the bone marrow, creating a leukemia-supportive microenvironment. This alteration promotes mechanisms of immunological evasion, enabling leukemic cells to escape from immune surveillance (Poveda-Garavito & Combita, 2023) [49]. The leukemic cells interact with various components of the BMME, including mesenchymal stem cells and immune cells, leading to significant changes in the phenotype and function of these cells, which further aids in the escape from immune recognition (Pastorczak et al., 2021) [53].

Moreover, the immune evasion mechanisms employed by leukemic cells include the overexpression of ligands for inhibitory receptors, which can diminish the activity of T cells and natural killer (NK) cells. For instance, leukemic cells can engage anti-phagocytic receptors on macrophages and inhibit NK cell activity through various immune checkpoints (Pastorczak et al., 2021) [53]. This results in a significant impairment of the immune system's ability to recognize and eliminate leukemic cells.

In acute myeloid leukemia (AML), the BMME similarly supports leukemic cell survival through metabolic adaptations that promote immune evasion. The metabolic landscape of AML is characterized by altered energy allocation and oxygen utilization, which not only supports leukemic progenitor cells but also affects the functionality of immune cells within the microenvironment (Xu et al., 2022) [54]. The metabolic mechanisms orchestrated by leukemia cells create a milieu that is immunosuppressive, thereby contributing to treatment resistance (Xu et al., 2021) [55].

The interactions between leukemic cells and the BMME also involve the regulation of immune cell behaviors through direct cell-to-cell contact and soluble factors, further complicating the immune response. For example, the secretion of inflammatory cytokines from bone marrow stromal cells can exacerbate immune dysregulation and support the proliferation of leukemic clones (Sharifi et al., 2024) [56]. This intricate interplay between leukemic cells and the immune microenvironment not only facilitates the disease's progression but also presents challenges in treatment efficacy, highlighting the need for novel therapeutic strategies that target these interactions.

In summary, the development and progression of leukemia are intricately linked to the modifications of the bone marrow microenvironment and the immune evasion mechanisms employed by leukemic cells. These factors contribute to the establishment of a supportive niche for leukemia, which is characterized by altered immune dynamics and metabolic adaptations, ultimately leading to challenges in effective treatment and increased resistance. Understanding these processes is crucial for developing more effective therapeutic approaches aimed at restoring normal immune function and targeting the leukemia-supportive microenvironment.

5.3 Interaction Between Leukemic Cells and the Immune System ​

Leukemia, particularly acute lymphoblastic leukemia (ALL), develops and progresses through complex interactions between leukemic cells and the bone marrow microenvironment (BMME), as well as the immune system. The BMME serves as a crucial niche where both normal and leukemic hematopoietic stem cells interact with various stromal and immune cells. This interaction is pivotal in regulating hematopoiesis, and it is significantly altered in the presence of leukemic cells.

Leukemic cells can hijack the BMME, disrupting its physiological functions and creating a supportive microenvironment for their own survival and proliferation. They achieve this by altering the phenotype and function of both stromal and immune cells within the BMME. For instance, leukemic cells can induce functional defects in mesenchymal stem cells (MSCs), which are essential for maintaining the normal hematopoietic niche. Studies have shown that leukemia-associated MSCs exhibit reduced self-renewal capacity and alterations in inflammatory signaling pathways, contributing to an environment that favors leukemic cell survival (Hughes et al. 2023) [50].

Furthermore, leukemic cells can engage in a reciprocal relationship with adipocytes in the BMME. These adipocytes are no longer passive components; instead, they actively supply leukemic cells with metabolic fuels and secrete adipokines that influence leukemic cell proliferation and resistance to chemotherapy. This metabolic interplay not only enhances the survival of leukemic cells but also creates a sanctuary that protects them from immune surveillance and therapeutic interventions (Higos et al. 2025) [52].

The immune system's response to leukemic cells is also significantly compromised. Leukemic cells employ various mechanisms to evade immune detection, such as altering the expression of ligands for inhibitory receptors on immune cells, thereby diminishing their ability to recognize and eliminate the leukemic cells. This immune evasion is a critical factor in the progression of leukemia, as it allows leukemic cells to proliferate unchecked within the BMME (Pastorczak et al. 2021) [53].

Moreover, the BMME can mediate the development of drug resistance in leukemia. Interactions between leukemic cells and the microenvironment can provide protective signals that shield leukemic cells from the cytotoxic effects of chemotherapy. For instance, the secretion of inflammatory cytokines by stromal cells can enhance the survival and proliferation of leukemic clones, complicating treatment outcomes (Zhang et al. 2019) [57].

In summary, the development and progression of leukemia are deeply intertwined with the dynamics of the bone marrow microenvironment and the immune system. The ability of leukemic cells to manipulate their surroundings, evade immune responses, and resist therapeutic interventions underscores the complexity of leukemia as a disease and highlights the need for innovative therapeutic strategies that target these interactions. Understanding these mechanisms is crucial for developing more effective treatments and improving patient outcomes in leukemia (Poveda-Garavito and Combita 2023) [49].

6 Current and Emerging Therapeutic Strategies ​

6.1 Conventional Chemotherapy ​

Leukemia, a group of hematological malignancies, develops through a complex interplay of genetic alterations that lead to the abnormal proliferation of hematopoietic cells. The pathogenesis of leukemia is characterized by dynamic changes in the genome, including chromosomal translocations and point mutations that result in the production of oncogenes and the inactivation of tumor suppressor genes. These genetic mutations disrupt the balance between cell proliferation, differentiation, and apoptosis, ultimately contributing to the disease's progression and relapse [58].

The progression of leukemia is often fueled by leukemia stem cells (LSCs), which represent a reservoir of malignant cells resistant to conventional therapies. LSCs exhibit properties such as self-renewal and differentiation, which enable them to survive chemotherapy and contribute to disease relapse [59][60]. Research has shown that LSCs evolve during disease progression, acquiring mutations and alterations in signaling pathways that promote their survival and resistance to treatment [61]. Specifically, the interaction between LSCs and their microenvironment, such as the bone marrow niche, plays a critical role in their persistence and therapeutic recalcitrance [62].

Conventional chemotherapy has been the cornerstone of leukemia treatment, employing cytotoxic agents to target rapidly dividing cells. However, this approach is often non-specific and can lead to significant toxicity, as it affects both malignant and healthy cells [63]. Despite its efficacy in many cases, the limitations of chemotherapy include the development of drug resistance, systemic toxicities, and the inability to eradicate LSCs, which can lead to relapse [64].

In light of these challenges, there has been a shift towards targeted therapies that aim to disrupt the molecular pathways critical for leukemia pathogenesis. For example, targeted agents have been developed to inhibit specific fusion proteins arising from chromosomal translocations, such as PML-RARα in acute promyelocytic leukemia and BCR-ABL in chronic myeloid leukemia [58][65]. These advancements have significantly improved patient outcomes, transforming previously fatal conditions into manageable diseases.

In summary, leukemia develops through a series of genetic alterations that lead to the abnormal proliferation of hematopoietic cells, with LSCs playing a pivotal role in disease progression and therapeutic resistance. While conventional chemotherapy remains a fundamental treatment strategy, its limitations have prompted the exploration of targeted therapies aimed at addressing the underlying mechanisms of leukemia, thus offering new hope for improved patient outcomes [64][66].

6.2 Targeted Therapies and Immunotherapies ​

Leukemia is characterized as a group of hematological malignancies marked by the abnormal proliferation, decreased apoptosis, and impeded differentiation of hematopoietic stem/progenitor cells. The development and progression of leukemia involve dynamic changes in the genome, primarily through chromosomal translocations and point mutations. These genetic alterations lead to the production of oncogenes with dominant gain of function and tumor suppressor genes with recessive loss of function. Notably, the most common chromosomal translocations in myeloid leukemia include t(15;17) which generates PML-RARα, t(8;21) that produces AML1-ETO, and t(9;22) which generates BCR-ABL. These genetic events disrupt the delicate balance between cell proliferation, differentiation, and apoptosis, culminating in the leukemic phenotype (Chen & Zhou 2012; Ikeda et al. 2006).

The treatment landscape for leukemia has evolved significantly over the past few decades, particularly with the advent of targeted therapies. These therapies aim to disrupt the molecular pathways critical for leukemia pathogenesis, providing a more precise treatment approach compared to traditional chemotherapy. For instance, All Trans Retinoic Acid (ATRA) has shown remarkable success in treating acute promyelocytic leukemia, while imatinib has been effective against chronic myeloid leukemia (CML) by specifically targeting the BCR-ABL fusion protein (Ikeda et al. 2006; Downing 2008). However, the complexity of leukemia's pathogenesis, including the presence of leukemia stem cells (LSCs) that are resistant to current treatments, presents significant challenges. LSCs contribute to disease progression and relapse by exhibiting aberrant self-renewal and survival capabilities, often leading to treatment resistance (Crews & Jamieson 2012).

Recent advances in biotechnology have led to the development of new targeted therapies and combination strategies that aim to improve patient outcomes. Current research is exploring the integration of molecularly targeted agents with immunotherapeutic approaches. Immunotherapy, particularly through the use of Chimeric Antigen Receptor (CAR)-T cell therapy, has shown promise in transforming the treatment landscape for leukemia. This strategy focuses on enhancing the immune response against leukemia cells, though challenges such as T cell exhaustion and the immunosuppressive tumor microenvironment remain significant hurdles (Hushmandi et al. 2025; Maurer et al. 2022).

Combination therapies that integrate targeted agents with immunotherapies are gaining traction as they may enhance therapeutic efficacy and mitigate resistance. This approach aims to address the multifaceted nature of leukemia by simultaneously targeting the malignant cells and modulating the immune system (Zhong et al. 2025; Santoro et al. 2024). Furthermore, the exploration of novel therapeutic strategies, including gene editing and epigenetic modulators, is underway, which may further refine treatment options and improve clinical outcomes for patients suffering from this challenging disease (Shahid et al. 2025).

In conclusion, the development and progression of leukemia are driven by complex genetic alterations that disrupt normal hematopoietic processes. While targeted therapies have made significant strides in treating specific leukemia subtypes, the persistent challenges posed by LSCs and treatment resistance necessitate ongoing research into combination therapies and novel immunotherapeutic strategies. The integration of these approaches holds the potential to improve patient outcomes and pave the way for more effective treatments in the future.

6.3 Advances in Personalized Medicine ​

Leukemia is characterized as a malignant tumor with high heterogeneity and a complex evolutionary process, making its development and progression particularly challenging to understand. Traditional bulk sequencing techniques have been inadequate in resolving the heterogeneity and clonal evolution of leukemia cells, which has hindered a comprehensive understanding of the mechanisms driving leukemia development and the identification of potential therapeutic targets. However, the advent of single-cell sequencing technology has enabled researchers to investigate the gene expression profiles, mutations, and epigenetic features of leukemia at the single-cell level, thereby providing new insights into leukemia research and potential therapeutic strategies [67].

The pathogenesis of leukemia involves a multistep process that includes the accumulation of genetic alterations over time. These genetic mutations disrupt the delicate balance between cell proliferation, differentiation, and apoptosis, leading to the malignant transformation of hematopoietic cells. Recent studies have highlighted the critical role of leukemia stem cells (LSCs) in this process. LSCs are thought to be responsible for the initiation and maintenance of leukemia, and their interactions with the bone marrow microenvironment contribute to therapeutic resistance [65], [68].

Current therapeutic strategies for leukemia have primarily focused on traditional treatments such as chemotherapy, radiotherapy, and hematopoietic stem cell transplantation. While these approaches have improved patient outcomes, they are often limited by non-specificity, drug resistance, and relapse. Consequently, there has been a shift towards targeted therapies, which aim to exploit specific molecular alterations within different leukemia subtypes. The development of molecularly targeted agents represents a significant breakthrough in precision medicine for leukemia, although challenges such as resistance to targeted drugs and tumor heterogeneity remain significant obstacles [64].

Advances in personalized medicine have emerged as a promising avenue for enhancing therapeutic efficacy in leukemia treatment. With the increasing understanding of the molecular mechanisms underlying leukemia, personalized strategies are being developed that target specific genetic and epigenetic alterations within leukemic cells. For instance, recent advancements in genetic, epigenetic, and metabolic profiling have opened opportunities for personalized treatment strategies that may improve outcomes for patients with acute myelogenous leukemia (AML) [69]. Furthermore, ongoing research is exploring the integration of targeted agents with other therapeutic modalities, such as immunotherapy and novel drug combinations, to enhance treatment efficacy and mitigate resistance [64].

In summary, leukemia develops through a complex interplay of genetic alterations and microenvironmental interactions, with LSCs playing a pivotal role in its pathogenesis. Current therapeutic strategies are evolving from traditional methods to more personalized and targeted approaches, reflecting the advancements in understanding leukemia's molecular underpinnings. As research progresses, the potential for more effective and individualized treatments for leukemia continues to expand, paving the way for improved patient outcomes.

7 Conclusion ​

The development and progression of leukemia represent a multifaceted interplay of genetic, epigenetic, and environmental factors, underscoring the complexity of this group of hematological malignancies. Key findings from recent research highlight the critical role of genetic mutations, such as chromosomal translocations and specific oncogene alterations, in driving the leukemogenic process across various leukemia subtypes, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). Additionally, epigenetic modifications have emerged as significant contributors to leukemia pathogenesis, influencing gene expression and cellular behavior. Environmental factors, including chemical exposures and lifestyle choices, further complicate the etiology of leukemia, emphasizing the need for a holistic understanding of risk factors. The bone marrow microenvironment plays a pivotal role in leukemia progression, facilitating immune evasion and contributing to therapeutic resistance. Current and emerging therapeutic strategies, including targeted therapies and immunotherapies, are evolving towards more personalized approaches that aim to address the unique molecular characteristics of each patient's leukemia. Future research should focus on elucidating the intricate interactions between genetic, epigenetic, and environmental factors, as well as the development of innovative therapeutic modalities that enhance treatment efficacy and improve patient outcomes. Overall, the path to better management of leukemia lies in a comprehensive understanding of its complex biology and the integration of personalized medicine into clinical practice.

References ​

  • [1] Luana Bavaro;Margherita Martelli;Michele Cavo;Simona Soverini. Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update.. International journal of molecular sciences(IF=4.9). 2019. PMID:31817512. DOI: 10.3390/ijms20246141.
  • [2] Ningxuan Wang;Xiangan Li;Chenyang She;Jun Zhang. Research progress on the mechanisms of CSF3R mutations in leukemogenesis and treatment strategies.. Cancer cell international(IF=6.0). 2025. PMID:40813694. DOI: 10.1186/s12935-025-03941-5.
  • [3] Shirin Azizidoost;Ava Nasrolahi;Mohadeseh Sheykhi-Sabzehpoush;Amir Anbiyaiee;Seyed Esmaeil Khoshnam;Maryam Farzaneh;Shahab Uddin. Signaling pathways governing the behaviors of leukemia stem cells.. Genes & diseases(IF=9.4). 2024. PMID:37692500. DOI: 10.1016/j.gendis.2023.01.008.
  • [4] Hee-Seon Choi;Byoung Soo Kim;Sik Yoon;Sae-Ock Oh;Dongjun Lee. Leukemic Stem Cells and Hematological Malignancies.. International journal of molecular sciences(IF=4.9). 2024. PMID:38928344. DOI: 10.3390/ijms25126639.
  • [5] R D Irons;W S Stillman. The process of leukemogenesis.. Environmental health perspectives(IF=9.8). 1996. PMID:9118899. DOI: 10.1289/ehp.961041239.
  • [6] Joanna Kruk;Hassan Y Aboul-Enein. Reactive Oxygen and Nitrogen Species in Carcinogenesis: Implications of Oxidative Stress on the Progression and Development of Several Cancer Types.. Mini reviews in medicinal chemistry(IF=3.3). 2017. PMID:28245782. DOI: 10.2174/1389557517666170228115324.
  • [7] F Ayala;R Dewar;M Kieran;R Kalluri. Contribution of bone microenvironment to leukemogenesis and leukemia progression.. Leukemia(IF=13.4). 2009. PMID:19727127. DOI: 10.1038/leu.2009.175.
  • [8] Michael A Teitell;Pier Paolo Pandolfi. Molecular genetics of acute lymphoblastic leukemia.. Annual review of pathology(IF=34.5). 2009. PMID:18783329. DOI: 10.1146/annurev.pathol.4.110807.092227.
  • [9] Geoffrey Parriott;Barbara L Kee. E Protein Transcription Factors as Suppressors of T Lymphocyte Acute Lymphoblastic Leukemia.. Frontiers in immunology(IF=5.9). 2022. PMID:35514954. DOI: 10.3389/fimmu.2022.885144.
  • [10] Zixi Hong;Zimeng Wei;Tian Xie;Lin Fu;Jiaxing Sun;Fuling Zhou;Muhammad Jamal;Qiuping Zhang;Liang Shao. Targeting chemokines for acute lymphoblastic leukemia therapy.. Journal of hematology & oncology(IF=40.4). 2021. PMID:33743810. DOI: 10.1186/s13045-021-01060-y.
  • [11] Valentina Ramírez Maldonado;Josgrey Navas Acosta;Iván Maldonado Marcos;Ángela Villaverde Ramiro;Alberto Hernández-Sánchez;Jesús M Hernández Rivas;Rocío Benito Sánchez. Unraveling the Genetic Heterogeneity of Acute Lymphoblastic Leukemia Based on NGS Applications.. Cancers(IF=4.4). 2024. PMID:39682152. DOI: 10.3390/cancers16233965.
  • [12] R Crazzolara;L Bendall. Emerging treatments in acute lymphoblastic leukemia.. Current cancer drug targets(IF=3.5). 2009. PMID:19200049. DOI: 10.2174/156800909787314057.
  • [13] Luca Pagliaro;Sai-Juan Chen;Daniel Herranz;Cristina Mecucci;Christine J Harrison;Charles G Mullighan;Ming Zhang;Zhu Chen;Nicolas Boissel;Stuart S Winter;Giovanni Roti. Acute lymphoblastic leukaemia.. Nature reviews. Disease primers(IF=60.6). 2024. PMID:38871740. DOI: 10.1038/s41572-024-00525-x.
  • [14] Maria Mesuraca;Nicola Amodio;Emanuela Chiarella;Stefania Scicchitano;Annamaria Aloisio;Bruna Codispoti;Valeria Lucchino;Ylenia Montalcini;Heather M Bond;Giovanni Morrone. Turning Stem Cells Bad: Generation of Clinically Relevant Models of Human Acute Myeloid Leukemia through Gene Delivery- or Genome Editing-Based Approaches.. Molecules (Basel, Switzerland)(IF=4.6). 2018. PMID:30126100. DOI: 10.3390/molecules23082060.
  • [15] T Bochtler;S Fröhling;A Krämer. Role of chromosomal aberrations in clonal diversity and progression of acute myeloid leukemia.. Leukemia(IF=13.4). 2015. PMID:25673237. DOI: 10.1038/leu.2015.32.
  • [16] Meriem Ben Khoud;Tiziano Ingegnere;Bruno Quesnel;Suman Mitra;Carine Brinster. Acute Myeloid Leukemia: Is It T Time?. Cancers(IF=4.4). 2021. PMID:34069204. DOI: 10.3390/cancers13102385.
  • [17] Michela Luciano;Peter W Krenn;Jutta Horejs-Hoeck. The cytokine network in acute myeloid leukemia.. Frontiers in immunology(IF=5.9). 2022. PMID:36248849. DOI: 10.3389/fimmu.2022.1000996.
  • [18] Jens Schrezenmeier;B J P Huntly. Epigenetic dysregulation in acute myeloid leukemia.. Seminars in hematology(IF=4.1). 2025. PMID:40651916. DOI: 10.1053/j.seminhematol.2025.06.003.
  • [19] Nandini Pal Basak;Subrata Banerjee. Mitochondrial dependency in progression of acute myeloid leukemia.. Mitochondrion(IF=4.5). 2015. PMID:25640960. DOI: .
  • [20] Aisha Masood;Mohammad A Shahshahan;Ali R Jazirehi. Novel approaches to modulate apoptosis resistance: basic and clinical implications in the treatment of chronic lymphocytic leukemia (CLL).. Current drug delivery(IF=3.0). 2012. PMID:22023214. DOI: 10.2174/156720112798376050.
  • [21] Suping Zhang;Thomas J Kipps. The pathogenesis of chronic lymphocytic leukemia.. Annual review of pathology(IF=34.5). 2014. PMID:23987584. DOI: 10.1146/annurev-pathol-020712-163955.
  • [22] Thomas J Kipps;Freda K Stevenson;Catherine J Wu;Carlo M Croce;Graham Packham;William G Wierda;Susan O'Brien;John Gribben;Kanti Rai. Chronic lymphocytic leukaemia.. Nature reviews. Disease primers(IF=60.6). 2017. PMID:28102226. DOI: 10.1038/nrdp.2016.96.
  • [23] Yiqing Cai;Lili Feng;Xin Wang. Targeting the tumor promoting effects of adenosine in chronic lymphocytic leukemia.. Critical reviews in oncology/hematology(IF=5.6). 2018. PMID:29759563. DOI: 10.1016/j.critrevonc.2018.03.022.
  • [24] Nathan Dubois;Emerence Crompot;Nathalie Meuleman;Dominique Bron;Laurence Lagneaux;Basile Stamatopoulos. Importance of Crosstalk Between Chronic Lymphocytic Leukemia Cells and the Stromal Microenvironment: Direct Contact, Soluble Factors, and Extracellular Vesicles.. Frontiers in oncology(IF=3.3). 2020. PMID:32974152. DOI: 10.3389/fonc.2020.01422.
  • [25] A Bresin;L D'Abundo;M G Narducci;M T Fiorenza;C M Croce;M Negrini;G Russo. TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia.. Cell death & disease(IF=9.6). 2016. PMID:26821067. DOI: 10.1038/cddis.2015.419.
  • [26] Nancy Nisticò;Domenico Maisano;Enrico Iaccino;Eleonora Vecchio;Giuseppe Fiume;Salvatore Rotundo;Ileana Quinto;Selena Mimmi. Role of Chronic Lymphocytic Leukemia (CLL)-Derived Exosomes in Tumor Progression and Survival.. Pharmaceuticals (Basel, Switzerland)(IF=4.8). 2020. PMID:32937811. DOI: 10.3390/ph13090244.
  • [27] Lisa Pfeuffer;Viola Siegert;Riccardo Trozzo;Katja Steiger;Roland Rad;Jürgen Ruland;Maike Buchner. Autoimmunity promotes chronic lymphocytic leukemia progression in an indolent disease model.. Scientific reports(IF=3.9). 2025. PMID:39900937. DOI: 10.1038/s41598-025-86876-1.
  • [28] Chiara Cavallini;Roberto Chignola;Ilaria Dando;Omar Perbellini;Elda Mimiola;Ornella Lovato;Carlo Laudanna;Giovanni Pizzolo;Massimo Donadelli;Maria Teresa Scupoli. Low catalase expression confers redox hypersensitivity and identifies an indolent clinical behavior in CLL.. Blood(IF=23.1). 2018. PMID:29467184. DOI: 10.1182/blood-2017-08-800466.
  • [29] Afaf E G Osman;Michael W Deininger. Chronic Myeloid Leukemia: Modern therapies, current challenges and future directions.. Blood reviews(IF=5.7). 2021. PMID:33773846. DOI: 10.1016/j.blre.2021.100825.
  • [30] Giovanni Amabile;Annalisa Di Ruscio;Fabian Müller;Robert S Welner;Henry Yang;Alexander K Ebralidze;Hong Zhang;Elena Levantini;Lihua Qi;Giovanni Martinelli;Thijn Brummelkamp;Michelle M Le Beau;Maria E Figueroa;Christoph Bock;Daniel G Tenen. Dissecting the role of aberrant DNA methylation in human leukaemia.. Nature communications(IF=15.7). 2015. PMID:25997600. DOI: 10.1038/ncomms8091.
  • [31] Fabien Muselli;Jean-François Peyron;Didier Mary. Druggable Biochemical Pathways and Potential Therapeutic Alternatives to Target Leukemic Stem Cells and Eliminate the Residual Disease in Chronic Myeloid Leukemia.. International journal of molecular sciences(IF=4.9). 2019. PMID:31717629. DOI: 10.3390/ijms20225616.
  • [32] A Di Bacco;K Keeshan;S L McKenna;T G Cotter. Molecular abnormalities in chronic myeloid leukemia: deregulation of cell growth and apoptosis.. The oncologist(IF=4.2). 2000. PMID:11040277. DOI: 10.1634/theoncologist.5-5-405.
  • [33] P Torres-Barrera;H Mayani;A Chávez-González. Understanding the hematopoietic microenvironment in chronic myeloid leukemia: A concise review.. Current research in translational medicine(IF=3.0). 2021. PMID:33962119. DOI: 10.1016/j.retram.2021.103295.
  • [34] Bilal Abdulmawjood;Beatriz Costa;Catarina Roma-Rodrigues;Pedro V Baptista;Alexandra R Fernandes. Genetic Biomarkers in Chronic Myeloid Leukemia: What Have We Learned So Far?. International journal of molecular sciences(IF=4.9). 2021. PMID:34830398. DOI: 10.3390/ijms222212516.
  • [35] Yufei Zhang;Wenbin Yu;Dingding Yuan;Wenqi Ma;Yayi Tu;Bin He. Epigenetic therapy for leukemias: a comprehensive review from biological markers to practice.. Biotechnology advances(IF=12.5). 2025. PMID:40523510. DOI: 10.1016/j.biotechadv.2025.108626.
  • [36] Fatemeh Memari;Zeinab Joneidi;Behnaz Taheri;Sedigheh Fekri Aval;Amir Roointan;Nosratollah Zarghami. Epigenetics and Epi-miRNAs: Potential markers/therapeutics in leukemia.. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie(IF=7.5). 2018. PMID:30170355. DOI: 10.1016/j.biopha.2018.07.133.
  • [37] Reza Ranjbar;Ansar Karimian;Arad Aghaie Fard;Mehdi Tourani;Maryam Majidinia;Farhad Jadidi-Niaragh;Bahman Yousefi. The importance of miRNAs and epigenetics in acute lymphoblastic leukemia prognosis.. Journal of cellular physiology(IF=4.0). 2019. PMID:29384211. DOI: 10.1002/jcp.26510.
  • [38] Inés González-Herrero;Guillermo Rodríguez-Hernández;Andrea Luengas-Martínez;Marta Isidro-Hernández;Rafael Jiménez;Maria Begoña García-Cenador;Francisco Javier García-Criado;Isidro Sánchez-García;Carolina Vicente-Dueñas. The Making of Leukemia.. International journal of molecular sciences(IF=4.9). 2018. PMID:29772764. DOI: 10.3390/ijms19051494.
  • [39] Ezzatollah Fathi;Raheleh Farahzadi;Soheila Montazersaheb;Yasin Bagheri. Epigenetic Modifications in Acute Lymphoblastic Leukemia: From Cellular Mechanisms to Therapeutics.. Current gene therapy(IF=3.3). 2021. PMID:33183201. DOI: 10.2174/1566523220999201111194554.
  • [40] Elliot Stieglitz;Mignon L Loh. Genetic predispositions to childhood leukemia.. Therapeutic advances in hematology(IF=3.1). 2013. PMID:23926459. DOI: 10.1177/2040620713498161.
  • [41] Satoshi Saida. Predispositions to Leukemia in Down Syndrome and Other Hereditary Disorders.. Current treatment options in oncology(IF=4.7). 2017. PMID:28580501. DOI: 10.1007/s11864-017-0485-x.
  • [42] Ana Casado-García;Marta Isidro-Hernández;Silvia Alemán-Arteaga;Belén Ruiz-Corzo;Susana Riesco;Pablo Prieto-Matos;Lucía Sánchez;Isidro Sánchez-García;Carolina Vicente-Dueñas. Lessons from mouse models in the impact of risk factors on the genesis of childhood B-cell leukemia.. Frontiers in immunology(IF=5.9). 2023. PMID:37901253. DOI: 10.3389/fimmu.2023.1285743.
  • [43] Cameron K Tebbi. Etiology of Acute Leukemia: A Review.. Cancers(IF=4.4). 2021. PMID:34066700. DOI: 10.3390/cancers13092256.
  • [44] David A Eastmond;Nagalakshmi Keshava;Babasaheb Sonawane. Lymphohematopoietic cancers induced by chemicals and other agents and their implications for risk evaluation: An overview.. Mutation research. Reviews in mutation research(IF=4.2). 2014. PMID:24731989. DOI: 10.1016/j.mrrev.2014.04.001.
  • [45] M-W Jin;S-M Xu;Q An;P Wang. A review of risk factors for childhood leukemia.. European review for medical and pharmacological sciences(IF=3.3). 2016. PMID:27735044. DOI: .
  • [46] Maryam Shahbaz;Amna Basharat;Rehana Yasmin;Nafees Ahmad;Rashada Abbasi;Shujaat Hussain. Leveraging Explainable AI for Early Risk Prediction and Type Classification for Leukemia: Insights Using Clinical Data From Pakistan.. IEEE journal of biomedical and health informatics(IF=6.8). 2025. PMID:40031230. DOI: 10.1109/JBHI.2025.3531294.
  • [47] Peter F Infante. Residential Proximity to Gasoline Stations and Risk of Childhood Leukemia.. American journal of epidemiology(IF=4.8). 2017. PMID:27923798. DOI: 10.1093/aje/kww130.
  • [48] Janine-Alison Schmidt;Sabine Hornhardt;Friederike Erdmann;Isidro Sánchez-García;Ute Fischer;Joachim Schüz;Gunde Ziegelberger. Risk Factors for Childhood Leukemia: Radiation and Beyond.. Frontiers in public health(IF=3.4). 2021. PMID:35004601. DOI: 10.3389/fpubh.2021.805757.
  • [49] Nathaly Poveda-Garavito;Alba Lucía Combita. Contribution of the TIME in BCP-ALL: the basis for novel approaches therapeutics.. Frontiers in immunology(IF=5.9). 2023. PMID:38299154. DOI: 10.3389/fimmu.2023.1325255.
  • [50] Anastasia M Hughes;Vincent Kuek;Joyce Oommen;Grace-Alyssa Chua;Maria van Loenhout;Sebastien Malinge;Rishi S Kotecha;Laurence C Cheung. Characterization of mesenchymal stem cells in pre-B acute lymphoblastic leukemia.. Frontiers in cell and developmental biology(IF=4.3). 2023. PMID:36743421. DOI: 10.3389/fcell.2023.1005494.
  • [51] Guri Døsen-Dahl;Else Munthe;Marit Kveine Nygren;Heidi Stubberud;Marit E Hystad;Edith Rian. Bone marrow stroma cells regulate TIEG1 expression in acute lymphoblastic leukemia cells: role of TGFbeta/BMP-6 and TIEG1 in chemotherapy escape.. International journal of cancer(IF=4.7). 2008. PMID:18798273. DOI: 10.1002/ijc.23833.
  • [52] Romane Higos;Kevin Saitoski;Mathieu Hautefeuille;Geneviève Marcelin;Karine Clément;Nadine Varin-Blank;Christophe Breton;Simon Lecoutre;Mélanie Lambert. The Critical Role of Adipocytes in Leukemia.. Biology(IF=3.5). 2025. PMID:40563875. DOI: 10.3390/biology14060624.
  • [53] Agata Pastorczak;Krzysztof Domka;Klaudyna Fidyt;Martyna Poprzeczko;Malgorzata Firczuk. Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia.. Cancers(IF=4.4). 2021. PMID:33810515. DOI: 10.3390/cancers13071536.
  • [54] Binyan Xu;Ziying Zhou;Yueting Wen;Zhongwei Li;Zhongxi Huang;Yuhua Li. The immunometabolic landscape of the bone marrow microenvironment in acute myeloid leukemia.. Experimental hematology & oncology(IF=13.5). 2022. PMID:36307865. DOI: 10.1186/s40164-022-00332-8.
  • [55] Binyan Xu;Rong Hu;Zhao Liang;Tong Chen;Jianyu Chen;Yuxing Hu;Yirong Jiang;Yuhua Li. Metabolic regulation of the bone marrow microenvironment in leukemia.. Blood reviews(IF=5.7). 2021. PMID:33353770. DOI: 10.1016/j.blre.2020.100786.
  • [56] Mohammad Jafar Sharifi;Ling Xu;Nahid Nasiri;Mehnoosh Ashja-Arvan;Hadis Soleimanzadeh;Mazdak Ganjalikhani-Hakemi. Immune-dysregulation harnessing in myeloid neoplasms.. Cancer medicine(IF=3.1). 2024. PMID:39254117. DOI: 10.1002/cam4.70152.
  • [57] L-P Zhang;M-Y Zhang;W-J Liu. Mechanism of resistance and therapeutic prospect of leukemia mediated by signaling pathway in bone marrow microenvironment.. European review for medical and pharmacological sciences(IF=3.3). 2019. PMID:31378880. DOI: 10.26355/eurrev_201908_18523.
  • [58] Sai-Juan Chen;Guang-Biao Zhou. Targeted therapy: The new lease on life for acute promyelocytic leukemia, and beyond.. IUBMB life(IF=3.2). 2012. PMID:22714999. DOI: 10.1002/iub.1055.
  • [59] Leslie A Crews;Catriona H M Jamieson. Selective elimination of leukemia stem cells: hitting a moving target.. Cancer letters(IF=10.1). 2013. PMID:22906415. DOI: .
  • [60] Leslie A Crews;Catriona H M Jamieson. Chronic myeloid leukemia stem cell biology.. Current hematologic malignancy reports(IF=3.3). 2012. PMID:22467334. DOI: 10.1007/s11899-012-0121-6.
  • [61] Adolfo A Ferrando;Carlos López-Otín. Clonal evolution in leukemia.. Nature medicine(IF=50.0). 2017. PMID:28985206. DOI: 10.1038/nm.4410.
  • [62] Parinaz Zivarpour;Jamal Hallajzadeh;Zatollah Asemi;Fatemeh Sadoughi;Mehran Sharifi. Chitosan as possible inhibitory agents and delivery systems in leukemia.. Cancer cell international(IF=6.0). 2021. PMID:34663339. DOI: 10.1186/s12935-021-02243-w.
  • [63] Mohammad Sadra Harifi-Mood;Mahtab Daroudi;Majid Darroudi;Kobra Naseri;Saeed Samarghandian;Tahereh Farkhondeh. Targeting the NF-E2-related factor 2 pathway for overcoming leukemia.. International journal of biological macromolecules(IF=8.5). 2023. PMID:37890739. DOI: 10.1016/j.ijbiomac.2023.127594.
  • [64] Zhiyuan Zhong;Ran Yao;Yifei Duan;Cheng Ouyang;Zefan Du;Lindi Li;Hailin Zou;Yong Liu;Hongman Xue;Liang Li;Chun Chen. Advances and Challenges in Targeted Therapy and Its Combination Strategies for Leukemia.. Biomedicines(IF=3.9). 2025. PMID:40722724. DOI: 10.3390/biomedicines13071652.
  • [65] A Ikeda;D B Shankar;M Watanabe;F Tamanoi;T B Moore;K M Sakamoto. Molecular targets and the treatment of myeloid leukemia.. Molecular genetics and metabolism(IF=3.5). 2006. PMID:16678459. DOI: 10.1016/j.ymgme.2006.03.011.
  • [66] Zhuoya Wan;Runzi Sun;Pearl Moharil;Jing Chen;Yuzhe Liu;Xu Song;Qiang Ao. Research advances in nanomedicine, immunotherapy, and combination therapy for leukemia.. Journal of leukocyte biology(IF=3.1). 2021. PMID:33259068. DOI: 10.1002/JLB.5MR0620-063RR.
  • [67] Dan Xie;Bangquan An;Mingyue Yang;Lei Wang;Min Guo;Heng Luo;Shengwen Huang;Fa Sun. Application and research progress of single cell sequencing technology in leukemia.. Frontiers in oncology(IF=3.3). 2024. PMID:39267837. DOI: 10.3389/fonc.2024.1389468.
  • [68] Ivana Gojo;Judith E Karp. New strategies in acute myelogenous leukemia: leukemogenesis and personalized medicine.. Clinical cancer research : an official journal of the American Association for Cancer Research(IF=10.2). 2014. PMID:25324141. DOI: 10.1158/1078-0432.CCR-14-0900.
  • [69] Monica L Guzman;John N Allan. Concise review: Leukemia stem cells in personalized medicine.. Stem cells (Dayton, Ohio)(IF=3.6). 2014. PMID:24214290. DOI: 10.1002/stem.1597.

MaltSci Intelligent Research Services ​

Search for more papers on MaltSci.com ​

Leukemia · Genetic Factors · Epigenetics · Environmental Factors · Bone Marrow Microenvironment

© 2025 MaltSci