Review

Potential acute myeloid signaling pathways

Shazan Farhat 1*

1 Department of Computer Science, Faculty of Natural Science, Jamia Millia Islamia, New Delhi-110025 India.

* Correspondence: shazanfarhatt@gmail.com (S.F.)

Citation: Farhat, S. Potential acute myeloid signaling pathways. Glob. Jour. Bas. Sci. 2025, 1(6). 1-10.

Received: February 05, 2025

Revised: March 20, 2025

Accepted: April 19, 2025

Published: April 25, 2025

doi: 10.63454/jbs20000030

ISSN: 3049-3315

Volume 1; Issue 6

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Abstract: Acute myeloid leukemia (AML) is a biologically heterogeneous hematological malignancy characterized by the clonal expansion of immature myeloid progenitor cells, resulting in impaired differentiation, uncontrolled proliferation, altered cellular metabolism, and resistance to apoptosis. Despite recent advances in molecular diagnostics and targeted therapies, AML continues to be associated with high relapse rates and poor clinical outcomes, highlighting the need for a deeper understanding of its underlying molecular mechanisms. Accumulating evidence indicates that AML pathogenesis is driven by the aberrant activation and complex interplay of multiple intracellular signaling pathways that regulate normal hematopoietic cell fate decisions.  Key oncogenic signaling cascades implicated in AML include receptor tyrosine kinase–mediated pathways involving FLT3, KIT, and RAS, which activate downstream PI3K/AKT/mTOR and MAPK/ERK signaling to promote leukemic cell survival and proliferation. Cytokine-dependent JAK/STAT signaling contributes to leukemic stem cell maintenance and immune evasion, while developmental pathways such as Wnt/β-catenin, Hedgehog, and Notch are frequently dysregulated, reinforcing self-renewal and differentiation arrest. In addition, disruption of tumor suppressor signaling, particularly the p53 pathway, along with alterations in intrinsic and extrinsic apoptotic mechanisms, enables leukemic cells to evade programmed cell death and acquire therapeutic resistance.  This review provides a comprehensive overview of the major signaling pathways involved in AML, emphasizing their molecular mechanisms, functional crosstalk, and therapeutic relevance. Understanding these signaling networks is critical for the development of precision medicine strategies and novel targeted therapies to improve outcomes for patients with AML.

Keywords: Acute Myeloid Leukemia; signaling pathways; FLT3; PI3K/AKT; MAPK; JAK/STA; targeted therapy

1. Introduction

Acute Myeloid Leukemia (AML) is an aggressive and biologically heterogeneous hematological malignancy characterized by the clonal expansion of immature myeloid progenitor cells in the bone marrow, peripheral blood, and other tissues. This abnormal accumulation leads to impaired normal hematopoiesis, resulting in anemia, thrombocytopenia, and neutropenia, which are the major clinical manifestations of the disease [1-3]. AML represents the most common form of acute leukemia in adults and is associated with high morbidity and mortality, particularly in elderly patients, despite significant advances in diagnostic and therapeutic approaches.The pathogenesis of AML is driven by a complex interplay of genetic, epigenetic, and microenvironmental factors that converge on aberrant intracellular signaling pathways (Figure 1). Large-scale genomic studies have revealed that AML is not a single disease entity but rather a collection of molecularly distinct subtypes, each characterized by specific mutational profiles and altered signaling networks. These molecular alterations disrupt tightly regulated cellular processes such as proliferation, differentiation, apoptosis, metabolism, and self-renewal, ultimately promoting leukemic transformation and disease progression [3-7].

Traditionally, AML development has been described using a multistep leukemogenesis model, in which cooperating genetic lesions collectively drive malignant transformation. Mutations that enhance proliferative and survival signaling often coexist with those that impair differentiation and alter epigenetic regulation. Many of these mutations directly or indirectly affect intracellular signaling cascades, leading to constitutive activation or suppression of pathways that normally regulate hematopoietic stem and progenitor cell fate [8-17]. As a result, dysregulated signaling pathways are now recognized as central drivers of AML initiation, maintenance, and therapeutic resistance. Among the most extensively studied pathways in AML are receptor tyrosine kinase–mediated signaling networks, including those downstream of FMS-like tyrosine kinase 3 (FLT3), as well as key intracellular cascades such as the PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT pathways [13-20]. These signaling axes promote leukemic cell survival, uncontrolled proliferation, and resistance to apoptosis. In addition, developmental pathways such as Wnt/β-catenin, Hedgehog, and Notch have been implicated in the maintenance of leukemic stem cells (LSCs), a subpopulation of cells believed to be responsible for disease persistence and relapse. Tumor suppressor pathways, including p53-mediated signaling and intrinsic apoptotic pathways, are also frequently dysregulated, further contributing to genomic instability and treatment failure [21-24].

The clinical relevance of AML signaling pathways has been underscored by the recent success of targeted therapies. Small-molecule inhibitors targeting specific signaling components—such as FLT3 inhibitors and BCL-2 antagonists—have demonstrated significant clinical benefit, particularly when used in combination with conventional chemotherapy or hypomethylating agents. However, the development of resistance, pathway redundancy, and compensatory signaling remain major obstacles to long-term therapeutic success [21, 23]. These challenges highlight the need for a comprehensive understanding of AML-associated signaling networks and their interactions. 

In this review, we provide a detailed overview of the major signaling pathways implicated in AML pathogenesis, progression, and therapeutic resistance. We discuss the molecular mechanisms underlying pathway dysregulation, their biological and clinical significance, and current efforts to therapeutically target these pathways. A deeper understanding of AML signaling networks will be essential for the development of more effective, durable, and personalized treatment strategies.

2. Overview of AML pathogenesis: Acute Myeloid Leukemia (AML) arises from the malignant transformation of hematopoietic stem and progenitor cells (HSPCs), leading to uncontrolled proliferation, impaired differentiation, and accumulation of immature myeloid blasts in the bone marrow and peripheral blood. The resulting suppression of normal hematopoiesis  causes cytopenias and is responsible for the major clinical manifestations of AML, including infection, bleeding, and anemia. AML pathogenesis is complex and involves the interplay of genetic mutations, epigenetic dysregulation, altered signaling pathways, and microenvironmental influences [1-5].

Figure 1. An overview of AML.

2.1. Genetic alterations in AML: AML is characterized by a diverse spectrum of genetic abnormalities, including chromosomal translocations, copy number variations, and somatic gene mutations. Recurrent chromosomal rearrangements such as t(8;21), inv(16), and t(15;17) generate fusion proteins that disrupt transcriptional regulation and block myeloid differentiation. In addition, next-generation sequencing studies have identified frequent mutations in genes encoding signaling molecules (e.g., FLT3, RAS, KIT), transcription factors (e.g., RUNX1, CEBPA), and epigenetic regulators (e.g., DNMT3A, TET2, IDH1/2). The classical “two-hit” model of leukemogenesis proposes that AML develops through the cooperation of at least two classes of mutations. Class I mutations promote cell proliferation and survival by activating signaling pathways, whereas Class II mutations impair differentiation and enhance self-renewal. Although this model has evolved with the recognition of additional mutation classes, it remains a useful framework for understanding how genetic alterations cooperate to drive leukemic transformation [3,4,6].

2.2. Epigenetic dysregulation: Epigenetic alterations play a central role in AML pathogenesis by modifying chromatin structure and gene expression without altering the DNA sequence. Mutations in epigenetic regulators such as DNMT3A, TET2, ASXL1, and IDH1/2 are among the most common lesions in AML. These mutations disrupt DNA methylation and histone modification patterns, leading to aberrant transcriptional programs that favor leukemic cell survival and block differentiation. Notably, mutations in IDH1 and IDH2 result in the production of the oncometabolite 2-hydroxyglutarate, which inhibits DNA and histone demethylation enzymes, thereby reinforcing epigenetic repression of differentiation-associated genes. These findings underscore the importance of epigenetic mechanisms in AML initiation and progression [1-3].

2.3. Dysregulated signaling pathways: Genetic and epigenetic alterations in AML converge on aberrant activation of intracellular signaling pathways that regulate proliferation, apoptosis, metabolism, and self-renewal. Constitutive activation of receptor tyrosine kinases, particularly FLT3, leads to persistent signaling through the PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT pathways. These signaling cascades promote leukemic cell growth, inhibit apoptosis, and contribute to resistance to cytotoxic therapies. In addition to oncogenic signaling, tumor suppressor pathways such as p53-mediated DNA damage responses and intrinsic apoptotic signaling are frequently disrupted in AML. These alterations allow leukemic cells to tolerate genomic instability and evade programmed cell death, further accelerating disease progression [8-20].

2.3. Leukemic stem cells and disease evolution: A key feature of AML pathogenesis is the presence of leukemic stem cells (LSCs), a rare subpopulation of cells capable of self-renewal and disease propagation. LSCs share many properties with normal hematopoietic stem cells but harbor genetic and epigenetic abnormalities that confer a survival advantage. These cells are often resistant to chemotherapy and are believed to be responsible for minimal residual disease and relapse. AML pathogenesis is also shaped by clonal evolution, in which genetically distinct subclones emerge over time under selective pressures such as therapy and the bone marrow microenvironment. This dynamic process contributes to disease heterogeneity and therapeutic resistance, posing major challenges to effective treatment [1-3,7,9].

3. FLT3 Signaling pathway role in AML

FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase that plays a critical role in normal hematopoiesis by regulating the proliferation, survival, and differentiation of early hematopoietic stem and progenitor cells. FLT3 is expressed primarily on immature hematopoietic cells, and its activation by FLT3 ligand induces receptor dimerization and autophosphorylation, initiating downstream intracellular signaling cascades essential for controlled myeloid development. Dysregulation of FLT3 signaling is one of the most common and clinically significant molecular abnormalities in acute myeloid leukemia (AML) [25-31].

3.1. FLT3 mutations in AML: FLT3 mutations occur in approximately 30–35% of AML cases and are among the most frequent genetic lesions identified in the disease. The two major types of FLT3 mutations are internal tandem duplications (FLT3-ITD) within the juxtamembrane domain and point mutations within the tyrosine kinase domain (FLT3-TKD), most commonly involving the D835 residue. FLT3-ITD mutations lead to constitutive activation of the receptor in the absence of ligand binding, resulting in persistent downstream signaling. These mutations are strongly associated with high leukemic burden, increased relapse rates, and poor overall prognosis, particularly in patients with a high FLT3-ITD allelic ratio [26-30]. FLT3-TKD mutations also result in aberrant kinase activity, although their prognostic impact is more variable and context dependent. Both mutation types disrupt the normal regulatory mechanisms of FLT3 signaling, contributing to leukemogenesis and disease progression.

3.2. Downstream signaling pathways: Constitutively activated FLT3 triggers multiple downstream signaling pathways that collectively promote leukemic cell survival, proliferation, and resistance to apoptosis. One of the most critical pathways activated by FLT3 is the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which enhances cellular metabolism, protein synthesis, and survival. Activation of this pathway contributes to chemoresistance by inhibiting apoptotic signaling and promoting cell cycle progression. FLT3 signaling also activates the mitogen-activated protein kinase (MAPK)/ERK pathway, which drives leukemic cell proliferation and enhances responsiveness to growth signals. In parallel, aberrant FLT3 activity leads to constitutive activation of the JAK/STAT pathway, particularly STAT5, which regulates transcription of genes involved in cell survival, self-renewal, and cytokine independence. Persistent STAT5 activation is a hallmark of FLT3-ITD-positive AML and plays a key role in maintaining the leukemic phenotype [24,26,29,31-41].

3.3. Role in leukemic stem cells and disease Progression: FLT3 signaling has been implicated in the maintenance and expansion of leukemic stem cells (LSCs), which are responsible for disease initiation, minimal residual disease, and relapse. FLT3-ITD enhances self-renewal capacity and disrupts normal differentiation programs, allowing leukemic progenitors to acquire stem cell–like properties. Additionally, FLT3-driven signaling promotes genomic instability and clonal evolution, further contributing to disease aggressiveness and therapeutic resistance [25-31].

3.4. Therapeutic targeting of FLT3: The central role of FLT3 signaling in AML has made it a major therapeutic target. First-generation FLT3 inhibitors, such as midostaurin, demonstrated improved overall survival when combined with standard chemotherapy in newly diagnosed FLT3-mutated AML patients. Second-generation inhibitors, including gilteritinib and quizartinib, exhibit greater specificity and potency and have shown significant clinical efficacy in relapsed or refractory AML. Despite these advances, resistance to FLT3 inhibitors frequently emerges through secondary mutations, activation of alternative signaling pathways, or microenvironment-mediated protection. Combination therapies targeting FLT3 alongside downstream signaling pathways or apoptotic regulators are currently being explored to overcome resistance and improve treatment durability [29-31].

3.5. Clinical and biological implications: FLT3 signaling plays a pivotal role in AML pathogenesis by integrating genetic mutations with aberrant intracellular signaling networks. Its impact on leukemic cell biology, prognosis, and therapeutic response underscores the importance of continued investigation into FLT3-driven signaling mechanisms. A deeper understanding of FLT3 pathway interactions and resistance mechanisms will be essential for optimizing targeted therapies and improving outcomes for patients with AML [25-27].

4. PI3K/AKT/mTOR pathway in AML

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is a central regulator of cellular growth, metabolism, survival, and proliferation in both normal and malignant cells. In hematopoiesis, this pathway plays a critical role in maintaining the balance between quiescence and proliferation of hematopoietic stem and progenitor cells. Aberrant activation of the PI3K/AKT/mTOR pathway is a common feature of acute myeloid leukemia (AML) and contributes significantly to leukemogenesis, disease progression, and resistance to therapy.

4.1. Mechanisms of pathway activation in AML: In AML, the PI3K/AKT/mTOR pathway is frequently activated through upstream genetic and epigenetic alterations rather than direct mutations of core pathway components. Constitutive signaling is commonly driven by activating mutations in receptor tyrosine kinases such as FLT3-ITD, KIT, and RAS, as well as by autocrine and paracrine stimulation from cytokines in the bone marrow microenvironment. Additionally, loss or reduced expression of negative regulators such as phosphatase and tensin homolog (PTEN) further enhances pathway activation. Upon activation, PI3K generates phosphatidylinositol-3,4,5-trisphosphate (PIP3), leading to recruitment and phosphorylation of AKT. Activated AKT subsequently regulates multiple downstream targets involved in cell cycle progression, metabolism, and apoptosis. mTOR functions as a key downstream effector, integrating growth factor signaling with cellular nutrient and energy status through two distinct complexes, mTORC1 and mTORC2 [34-37].

4.2. Biological functions in AML cells: Aberrant PI3K/AKT/mTOR signaling promotes leukemic cell survival by inhibiting apoptotic pathways and enhancing the expression of anti-apoptotic proteins. AKT-mediated phosphorylation of pro-apoptotic factors such as BAD and activation of mTOR-dependent protein synthesis support sustained leukemic cell growth. Furthermore, this pathway plays a crucial role in metabolic reprogramming of AML cells, promoting glycolysis, lipid synthesis, and mitochondrial function to meet increased energy demands. The PI3K/AKT/mTOR pathway also contributes to increased proliferation and impaired differentiation of AML blasts. Activation of mTORC1 stimulates ribosomal biogenesis and protein translation, facilitating rapid cell division. Additionally, cross-talk between PI3K/AKT/mTOR signaling and other oncogenic pathways, including MAPK and JAK/STAT, amplifies leukemogenic signaling networks and enhances cellular adaptability [34-37].

4.3. Role in leukemic stem cells and drug resistance: Evidence suggests that PI3K/AKT/mTOR signaling is critical for the maintenance and survival of leukemic stem cells (LSCs). LSCs rely on this pathway to sustain self-renewal capacity and resist cytotoxic stress. Persistent activation of PI3K/AKT signaling has been associated with resistance to conventional chemotherapy and targeted agents, as it enables AML cells to evade apoptosis and adapt to therapeutic pressure. The bone marrow microenvironment further reinforces PI3K/AKT/mTOR activation through stromal interactions and cytokine signaling, creating a protective niche for AML cells. This microenvironment-mediated signaling contributes to minimal residual disease and relapse.

4.4. Therapeutic targeting of the PI3K/AKT/mTOR pathway: Given its central role in AML biology, the PI3K/AKT/mTOR pathway has emerged as an attractive therapeutic target. Multiple inhibitors targeting PI3K, AKT, and mTOR have been evaluated in preclinical and clinical studies. However, single-agent activity has generally been modest due to pathway redundancy and compensatory signaling mechanisms. Combination approaches targeting PI3K/AKT/mTOR alongside other oncogenic pathways or apoptotic regulators, such as BCL-2 inhibitors, have shown enhanced efficacy in preclinical models. Ongoing clinical trials are exploring these combination strategies to overcome resistance and improve therapeutic outcomes [33-37].

4.5. Clinical Implications: The PI3K/AKT/mTOR pathway represents a key signaling axis in AML pathogenesis, linking oncogenic mutations to altered cellular metabolism, survival, and therapeutic resistance. A deeper understanding of pathway regulation, cross-talk, and context-specific dependencies is essential for optimizing targeted therapeutic strategies and improving patient outcomes.

5. MAPK/ERK pathway in AML

The mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) signaling pathway is a highly conserved intracellular cascade that regulates essential cellular processes including proliferation, differentiation, survival, and stress responses. In normal hematopoiesis, MAPK/ERK signaling contributes to the regulation of myeloid cell development and cytokine-mediated growth responses. Dysregulation of this pathway is frequently observed in acute myeloid leukemia (AML) and plays a significant role in leukemogenesis, disease progression, and therapeutic resistance.

5.1. Mechanisms of MAPK/ERK activation in AML: Aberrant activation of the MAPK/ERK pathway in AML most commonly arises from mutations in upstream signaling components. Activating mutations in RAS genes (NRAS and KRAS) are detected in approximately 10–15% of AML cases and result in constitutive signaling through RAF, MEK, and ERK kinases. In addition, mutations or overexpression of receptor tyrosine kinases such as FLT3 and KIT can indirectly activate the MAPK/ERK cascade. Autocrine and paracrine cytokine signaling within the bone marrow microenvironment further contributes to sustained pathway activation. Once activated, ERK translocates to the nucleus where it regulates the transcription of genes involved in cell cycle progression, including cyclins and transcription factors such as MYC and ELK1. Persistent ERK activation promotes uncontrolled proliferation and survival of leukemic blasts.

5.2. Biological role in AML pathogenesis: MAPK/ERK signaling enhances AML cell proliferation by facilitating G1–S phase cell cycle transition and promoting growth factor–independent expansion. Additionally, this pathway contributes to leukemic cell survival by modulating apoptotic signaling, including phosphorylation and inactivation of pro-apoptotic proteins. MAPK/ERK activity has also been implicated in blocking myeloid differentiation, thereby reinforcing the immature phenotype characteristic of AML blasts. Cross-talk between MAPK/ERK signaling and other oncogenic pathways, such as PI3K/AKT/mTOR and JAK/STAT, further amplifies leukemogenic signaling networks. This redundancy allows AML cells to adapt to therapeutic stress and contributes to disease heterogeneity.

5.3. Role in drug resistance and leukemic stem cells: Activation of the MAPK/ERK pathway has been associated with resistance to both conventional chemotherapy and targeted therapies in AML. ERK-mediated survival signaling enables leukemic cells to withstand cytotoxic insults, while pathway activation within the bone marrow microenvironment provides additional protection. Emerging evidence suggests that MAPK/ERK signaling also supports leukemic stem cell (LSC) maintenance, promoting self-renewal and contributing to minimal residual disease and relapse.

5.4. Therapeutic targeting of MAPK/ERK signaling: Given its involvement in AML pathogenesis, the MAPK/ERK pathway has been explored as a therapeutic target. MEK inhibitors and ERK inhibitors have demonstrated preclinical activity in AML models, particularly in RAS-mutated disease. However, clinical efficacy of single-agent MAPK pathway inhibitors has been limited due to compensatory activation of parallel signaling pathways. Combination strategies targeting MAPK/ERK alongside FLT3, PI3K/AKT, or apoptotic pathways are currently under investigation to improve therapeutic outcomes. The MAPK/ERK pathway represents an important component of the signaling network driving AML pathogenesis. Its role in promoting proliferation, survival, and therapeutic resistance highlights the need for integrated treatment approaches that account for signaling pathway cross-talk and disease heterogeneity [38-41].

6. MAPK/ERK Pathway in AML

The mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) signaling pathway is a highly conserved intracellular cascade that regulates essential cellular processes including proliferation, differentiation, survival, and stress responses. In normal hematopoiesis, MAPK/ERK signaling contributes to the regulation of myeloid cell development and cytokine-mediated growth responses. Dysregulation of this pathway is frequently observed in acute myeloid leukemia (AML) and plays a significant role in leukemogenesis, disease progression, and therapeutic resistance.

6.1. Mechanisms of MAPK/ERK activation in AML: Aberrant activation of the MAPK/ERK pathway in AML most commonly arises from mutations in upstream signaling components. Activating mutations in RAS genes (NRAS and KRAS) are detected in approximately 10–15% of AML cases and result in constitutive signaling through RAF, MEK, and ERK kinases. In addition, mutations or overexpression of receptor tyrosine kinases such as FLT3 and KIT can indirectly activate the MAPK/ERK cascade. Autocrine and paracrine cytokine signaling within the bone marrow microenvironment further contributes to sustained pathway activation.Once activated, ERK translocates to the nucleus where it regulates the transcription of genes involved in cell cycle progression, including cyclins and transcription factors such as MYC and ELK1. Persistent ERK activation promotes uncontrolled proliferation and survival of leukemic blasts [40].

6.2. Biological role in AML pathogenesis: MAPK/ERK signaling enhances AML cell proliferation by facilitating G1–S phase cell cycle transition and promoting growth factor–independent expansion. Additionally, this pathway contributes to leukemic cell survival by modulating apoptotic signaling, including phosphorylation and inactivation of pro-apoptotic proteins. MAPK/ERK activity has also been implicated in blocking myeloid differentiation, thereby reinforcing the immature phenotype characteristic of AML blasts. Cross-talk between MAPK/ERK signaling and other oncogenic pathways, such as PI3K/AKT/mTOR and JAK/STAT, further amplifies leukemogenic signaling networks. This redundancy allows AML cells to adapt to therapeutic stress and contributes to disease heterogeneity.

6.3. Role in drug resistance and leukemic stem cells: Activation of the MAPK/ERK pathway has been associated with resistance to both conventional chemotherapy and targeted therapies in AML. ERK-mediated survival signaling enables leukemic cells to withstand cytotoxic insults, while pathway activation within the bone marrow microenvironment provides additional protection. Emerging evidence suggests that MAPK/ERK signaling also supports leukemic stem cell (LSC) maintenance, promoting self-renewal and contributing to minimal residual disease and relapse.

6.4. Therapeutic targeting of MAPK/ERK signaling: Given its involvement in AML pathogenesis, the MAPK/ERK pathway has been explored as a therapeutic target. MEK inhibitors and ERK inhibitors have demonstrated preclinical activity in AML models, particularly in RAS-mutated disease. However, clinical efficacy of single-agent MAPK pathway inhibitors has been limited due to compensatory activation of parallel signaling pathways. Combination strategies targeting MAPK/ERK alongside FLT3, PI3K/AKT, or apoptotic pathways are currently under investigation to improve therapeutic outcomes. The MAPK/ERK pathway represents an important component of the signaling network driving AML pathogenesis. Its role in promoting proliferation, survival, and therapeutic resistance highlights the need for integrated treatment approaches that account for signaling pathway cross-talk and disease heterogeneity.

7. JAK/STAT pathway in AML

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a critical mediator of cytokine and growth factor signaling in hematopoietic cells. This pathway plays an essential role in normal hematopoiesis by regulating cell proliferation, survival, differentiation, and immune function. In acute myeloid leukemia (AML), aberrant activation of the JAK/STAT pathway contributes to leukemogenesis, disease progression, and resistance to therapy, making it an important focus of mechanistic and therapeutic research.

7.1. Mechanisms of JAK/STAT activation in AML: In AML, constitutive JAK/STAT signaling is often driven by upstream oncogenic events rather than direct mutations in JAK or STAT genes. Activating mutations in receptor tyrosine kinases such as FLT3—particularly FLT3 internal tandem duplications (FLT3-ITD)—are a major source of persistent STAT5 activation. In addition, autocrine and paracrine cytokine signaling within the bone marrow microenvironment, including interleukins and granulocyte-macrophage colony-stimulating factor (GM-CSF), further sustains pathway activation. Although less frequent, direct mutations in JAK kinases and negative regulators of the pathway, such as suppressor of cytokine signaling (SOCS) proteins, have also been identified in subsets of AML. These alterations impair normal feedback inhibition, leading to prolonged STAT phosphorylation and nuclear translocation.

7.2. Biological functions in AML cells: Activated STAT proteins, particularly STAT3 and STAT5, translocate to the nucleus where they regulate the transcription of genes involved in cell survival, proliferation, and self-renewal. STAT5 activation promotes the expression of anti-apoptotic proteins such as BCL-XL and MCL-1, enhancing leukemic cell survival. STAT3 signaling contributes to immune evasion, metabolic reprogramming, and inflammatory signaling within the leukemic microenvironment. JAK/STAT signaling also plays a role in maintaining an undifferentiated phenotype in AML blasts by regulating transcriptional programs that inhibit myeloid maturation. Persistent pathway activation thus supports both leukemic cell expansion and differentiation blockade.

7.3. Role in leukemic stem cells and drug resistance: Emerging evidence indicates that JAK/STAT signaling is critical for the maintenance of leukemic stem cells (LSCs). STAT5, in particular, enhances self-renewal capacity and protects LSCs from apoptotic stress. Activation of this pathway has been associated with resistance to conventional chemotherapy and targeted therapies, as it enables AML cells to adapt to therapeutic pressure and survive in protective bone marrow niches. Furthermore, cross-talk between the JAK/STAT pathway and other oncogenic signaling networks, including PI3K/AKT/mTOR and MAPK/ERK, amplifies survival signaling and contributes to disease heterogeneity and relapse.

7.4. Therapeutic targeting of the JAK/STAT pathway: Given its role in AML pathogenesis, the JAK/STAT pathway represents a promising therapeutic target. JAK inhibitors have demonstrated activity in preclinical AML models, particularly in combination with other targeted agents. However, clinical responses to JAK inhibition alone have been limited, likely due to pathway redundancy and compensatory signaling. Novel therapeutic strategies aimed at directly targeting STAT proteins or combining JAK/STAT inhibitors with FLT3 inhibitors or apoptotic pathway modulators are currently under investigation. The JAK/STAT pathway plays a central role in mediating survival, self-renewal, and therapeutic resistance in AML. A comprehensive understanding of its regulation and interactions with other signaling pathways will be essential for the development of effective combination therapies and improved patient outcomes [42-44].

8. Wnt/β-Catenin signaling pathways in AML

The Wnt/β-catenin signaling pathway is a highly conserved developmental signaling cascade that regulates cell fate determination, proliferation, differentiation, and stem cell maintenance. In normal hematopoiesis, tightly controlled Wnt/β-catenin signaling is essential for hematopoietic stem cell (HSC) self-renewal and lineage commitment. However, aberrant activation of this pathway has been increasingly recognized as a critical driver of acute myeloid leukemia (AML) pathogenesis, particularly in the maintenance of leukemic stem cells (LSCs), disease progression, and therapeutic resistance [45-47]. Canonical Wnt signaling is initiated when Wnt ligands bind to Frizzled receptors and co-receptors of the low-density lipoprotein receptor-related protein (LRP) family. This interaction inhibits the β-catenin destruction complex, which includes glycogen synthase kinase-3β (GSK-3β), adenomatous polyposis coli (APC), and Axin, leading to stabilization and nuclear accumulation of β-catenin. In the nucleus, β-catenin associates with T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors to activate genes involved in proliferation and stemness.

In AML, aberrant Wnt/β-catenin signaling is often driven by epigenetic alterations, overexpression of Wnt ligands or receptors, and disruption of pathway regulators rather than direct mutations in core Wnt components. Crosstalk with oncogenic signaling pathways such as FLT3, PI3K/AKT, and MAPK further enhances β-catenin stability and transcriptional activity, contributing to persistent pathway activation. One of the most critical roles of Wnt/β-catenin signaling in AML is its involvement in the maintenance and self-renewal of LSCs. β-catenin activity is required for the initiation and propagation of leukemia in several experimental AML models. Elevated β-catenin signaling enhances stem cell–like properties, allowing leukemic cells to evade differentiation cues and sustain long-term clonogenic potential.

LSCs with active Wnt/β-catenin signaling exhibit increased resistance to chemotherapy, as this pathway promotes survival signaling and protects cells from apoptosis. Consequently, persistent Wnt pathway activation is associated with minimal residual disease and relapse following treatment. Beyond stem cell maintenance, Wnt/β-catenin signaling contributes to AML progression by promoting proliferation, inhibiting differentiation, and facilitating metabolic adaptation. β-catenin target genes include transcription factors and cell cycle regulators that support leukemic expansion. Additionally, Wnt signaling modulates interactions between AML cells and the bone marrow microenvironment, further enhancing leukemic cell survival and drug resistance.

Activation of the Wnt/β-catenin pathway has also been implicated in resistance to targeted therapies, as it provides an alternative survival route when other signaling pathways are inhibited. This redundancy underscores the importance of targeting Wnt signaling in combination with other therapeutic approaches. Given its central role in AML biology, the Wnt/β-catenin pathway has emerged as a promising therapeutic target. Several strategies are under investigation, including inhibition of Wnt ligand secretion, disruption of β-catenin–TCF interactions, and modulation of upstream regulators such as GSK-3β. Although clinical development of Wnt inhibitors has been challenging due to pathway complexity and toxicity concerns, selective targeting of Wnt signaling in LSCs represents a potential avenue for achieving durable remissions [45-47].

Wnt/β-catenin signaling is a key regulator of leukemic stemness, disease persistence, and therapeutic resistance in AML. A deeper understanding of its regulatory mechanisms and interactions with other oncogenic pathways will be essential for the development of effective combination therapies aimed at eradicating LSCs and preventing relapse.

9. Hedgehog signaling pathway:

The Hedgehog (Hh) signaling pathway is a highly conserved developmental signaling cascade that regulates cell differentiation, proliferation, and stem cell maintenance. In normal hematopoiesis, Hh signaling contributes to the regulation of hematopoietic stem cell (HSC) self-renewal and lineage commitment. Dysregulation of this pathway has been implicated in the pathogenesis of acute myeloid leukemia (AML), particularly in the maintenance of leukemic stem cells (LSCs), chemoresistance, and disease progression. Hh signaling is initiated when Hh ligands, such as Sonic Hedgehog (Shh), bind to the Patched (PTCH) receptor, relieving inhibition of the Smoothened (SMO) protein. Activated SMO triggers the downstream Gli family of transcription factors, which translocate to the nucleus to regulate target genes involved in proliferation and survival. In AML, aberrant Hh pathway activation often arises from overexpression of ligands or receptors, epigenetic alterations, or cross-talk with other oncogenic pathways including FLT3 and PI3K/AKT. Persistent Hh signaling enhances LSC survival, self-renewal, and resistance to apoptosis, contributing to minimal residual disease and relapse [48-50].

9.1. Notch signaling pathway: The Notch signaling pathway is another conserved developmental pathway that governs cell fate decisions, differentiation, and stem cell maintenance. Activation of the Notch pathway occurs when Notch receptors (Notch1–4) interact with membrane-bound ligands such as Jagged or Delta-like proteins. This interaction induces proteolytic cleavage of the Notch intracellular domain (NICD), which translocates to the nucleus and forms a transcriptional complex to regulate target gene expression. In AML, the role of Notch signaling is context-dependent and complex. While Notch activation can promote differentiation and apoptosis in certain AML subtypes, aberrant Notch signaling in LSCs can support self-renewal and survival. Dysregulated Notch signaling has also been linked to drug resistance and leukemia progression through modulation of downstream effectors such as HES1, c-MYC, and BCL-2 family members. Cross-talk between Notch and other pathways, including Wnt/β-catenin and PI3K/AKT, further reinforces the leukemic phenotype [51-52].

Both Hedgehog and Notch pathways play critical roles in sustaining leukemic stemness, survival, and chemoresistance. Hh signaling primarily contributes to the maintenance of LSCs and proliferative advantage, while Notch signaling exerts context-dependent effects on AML cell fate and survival. Aberrant activation of these pathways is associated with minimal residual disease, relapse, and poor prognosis.

Therapeutic inhibition of Hedgehog signaling using SMO inhibitors such as vismodegib and glasdegib has shown efficacy in preclinical AML models and early-phase clinical trials, particularly in combination with cytarabine or other chemotherapeutic agents. Similarly, targeting Notch signaling through γ-secretase inhibitors or monoclonal antibodies against Notch ligands and receptors is under investigation, with the goal of eliminating LSCs and overcoming drug resistance. Combination therapies targeting Hh, Notch, and other oncogenic pathways are emerging as promising strategies for AML treatment [53-55].

10. p53 and apoptotic pathways in AML

The p53 tumor suppressor and apoptotic signaling pathways play a critical role in maintaining cellular homeostasis by regulating DNA repair, cell cycle arrest, and programmed cell death. In normal hematopoiesis, these pathways ensure the elimination of damaged or aberrant cells. In acute myeloid leukemia (AML), dysregulation of p53 and apoptotic signaling is a hallmark of leukemogenesis, contributing to genomic instability, chemoresistance, and disease progression.

10.1. Role of p53 in AML: p53, often referred to as the “guardian of the genome,” is encoded by the TP53 gene and functions as a transcription factor regulating a variety of genes involved in cell cycle arrest, DNA repair, senescence, and apoptosis. Although TP53 mutations are relatively infrequent in de novo AML (~5–10%), they are enriched in therapy-related AML and complex karyotype AML, where they confer poor prognosis. Loss of functional p53 disrupts the DNA damage response and allows leukemic cells to proliferate despite genomic instability. In addition to mutations, p53 function can be compromised through overexpression of negative regulators such as MDM2 and MDM4, which promote ubiquitination and degradation of p53. Impaired p53 activity diminishes apoptosis and enhances survival of AML blasts, contributing to resistance against conventional chemotherapies and targeted therapies [56-59].

10.2. Apoptotic pathways in AML: Apoptosis, or programmed cell death, is a tightly regulated process governed by intrinsic (mitochondrial) and extrinsic (death receptor) pathways. In AML, dysregulation of both pathways is common and contributes to leukemic cell survival. The intrinsic pathway is regulated by the BCL-2 family of proteins, which includes pro-apoptotic members (e.g., BAX, BAK) and anti-apoptotic members (e.g., BCL-2, MCL-1) (Figure 2). Overexpression of anti-apoptotic proteins, particularly BCL-2, is frequently observed in AML and is associated with chemoresistance and poor clinical outcomes. The extrinsic apoptotic pathway, mediated by death receptors such as FAS and TRAIL-R, is also impaired in AML through downregulation of receptor expression or overexpression of inhibitors of apoptosis (IAPs). Disruption of apoptotic signaling allows AML blasts to evade programmed cell death, supporting disease persistence and relapse [60-61].   

Figure 2. Apoptotic signaling pathways in AML. Here, we could see that the intrinsic pathways and extrinsic pathways are shown linked with apoptosis or cell death.

10.3. Crosstalk between p53 and apoptotic pathways: p53 serves as a critical link between DNA damage sensing and apoptosis. Activation of p53 induces transcription of pro-apoptotic genes, including BAX, PUMA, and NOXA, promoting mitochondrial outer membrane permeabilization and caspase activation. Loss of p53 function disrupts this regulatory network, reducing the sensitivity of AML cells to DNA-damaging agents and targeted therapies. Furthermore, aberrant signaling through pathways such as PI3K/AKT, MAPK/ERK, and NF-κB can further inhibit apoptosis and enhance leukemic cell survival. Targeting dysregulated p53 and apoptotic pathways in AML is an area of active investigation. Strategies include the use of MDM2 inhibitors (e.g., idasanutlin) to restore p53 activity, BCL-2 inhibitors (e.g., venetoclax) to promote mitochondrial apoptosis, and combination therapies targeting multiple anti-apoptotic proteins. These approaches aim to sensitize AML cells to chemotherapy, overcome resistance, and eliminate leukemic stem cells.

Dysregulation of p53 and apoptotic pathways is a major determinant of prognosis in AML. TP53 mutations, overexpression of anti-apoptotic proteins, and impaired death receptor signaling are associated with chemoresistance, disease relapse, and poor overall survival. Restoration of apoptosis through targeted therapies represents a promising strategy to improve outcomes in high-risk AML subtypes.

11. Conclusions
Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy driven by complex genetic, epigenetic, and signaling abnormalities. The signaling pathways discussed in this review—including FLT3, PI3K/AKT/mTOR, MAPK/ERK, JAK/STAT, Wnt/β-catenin, Hedgehog, Notch, and p53/apoptotic pathways—play pivotal roles in leukemic transformation, proliferation, survival, stem cell maintenance, differentiation blockade, and therapeutic resistance. Dysregulation of these pathways enables AML cells to evade apoptosis, sustain self-renewal, adapt to microenvironmental cues, and resist conventional chemotherapy and targeted therapies.Understanding the intricate cross-talk between these pathways has provided critical insights into AML pathogenesis. For example, interactions between FLT3 and MAPK/ERK, or between Wnt/β-catenin and Hedgehog signaling, amplify survival and proliferation signals in leukemic blasts and leukemic stem cells (LSCs). Similarly, the impairment of tumor suppressors such as p53, combined with overactive anti-apoptotic signaling, exacerbates chemoresistance and contributes to poor clinical outcomes.From a therapeutic standpoint, targeting these pathways represents a promising strategy to overcome AML heterogeneity and treatment resistance. Several small-molecule inhibitors, monoclonal antibodies, and combination regimens have been developed to modulate pathway activity. For instance, FLT3 inhibitors, BCL-2 antagonists, JAK/STAT inhibitors, and Hedgehog or Wnt pathway modulators have shown preclinical and clinical efficacy, especially when used in combination to prevent compensatory pathway activation. However, clinical challenges persist due to pathway redundancy, compensatory signaling, and interpatient heterogeneity, emphasizing the need for precision medicine approaches guided by molecular profiling.

Future research should focus on elucidating the context-specific roles of these signaling pathways in AML subtypes, identifying reliable biomarkers for patient stratification, and developing rational combination therapies that target multiple oncogenic nodes simultaneously. Integrating pathway-targeted interventions with conventional chemotherapy, immunotherapy, and epigenetic therapies holds the potential to eradicate leukemic stem cells, reduce relapse rates, and improve overall survival in AML patients. In conclusion, a comprehensive understanding of AML signaling networks not only enhances our knowledge of disease biology but also provides a rational framework for the development of novel, mechanism-based therapeutic strategies. Targeted modulation of these pathways represents a critical avenue toward improving outcomes in this aggressive and clinically challenging leukemia.

Author Contributions: Conceptualisation, S.F.; software, S.F.; investigation, S.F.;  writing—original draft preparation, S.F.; writing—review and editing, S.F.; visualisation, S.F.; supervision, S.F.; project administration, S.F. The author has read and agreed to the published version of the manuscript.

Funding: Not applicable.

Acknowledgments: We are grateful to the Department of Computer Science, Faculty of Natural Science, Jamia Millia Islamia, New Delhi-110025 India for providing us all the facilities to carry out the entire work.

Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: All the related data are supplied in this work or have been referenced properly.

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