Review

Potential CML signalling pathways and the biomarkers

Rowaid Qahwaji 1*

1 Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 22233, Saudi Arabia.

* Correspondence: rgahwajy@kau.edu.sa (R.S.)

Citation: Qahwaji, R. Potential CML signalling pathways and the biomarkers. Glob. Jour. Bas. Sci. 2025, 1(12). 1-8.

Received: August 13, 2025

Revised: October 08, 2025

Accepted: October 16, 2025

Published: October 21, 2025

doi: 10.63454/jbs20000064

ISSN: 3049-3315

Volume 1; Issue 12

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Abstract: Chronic myeloid leukemia (CML) is a clonal malignancy originating from a hematopoietic stem cell, defined cytogenetically by the Philadelphia chromosome and molecularly by the BCR–ABL1 fusion gene. This oncogene encodes a constitutively active BCR-ABL1 tyrosine kinase, which acts as the primary molecular driver of the disease. Its dysregulated activity fundamentally disrupts normal cellular signaling, leading to the uncontrolled proliferation and accumulation of myeloid lineage cells in the bone marrow and peripheral blood.  The pathogenesis of CML is mediated through the BCR-ABL1 kinase’s activation of a complex network of downstream signaling cascades. Key pathways include JAK/STAT, PI3K/AKT/mTOR, RAS/MAPK, and those involving MYC and SRC family kinases. These pathways collectively promote leukemogenesis by enhancing cell cycle progression, providing sustained survival signals, inhibiting apoptotic mechanisms, and contributing to genomic instability. This aberrant signaling underpins the three clinical phases of CML: the initial chronic phase, followed by the more aggressive accelerated and blast crisis phases.  The introduction of BCR-ABL1-targeted tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, and nilotinib, has transformed CML into a largely manageable chronic condition for most patients. However, significant clinical challenges persist. These include primary and acquired TKI resistance, disease progression to blast crisis, the persistence of leukemia stem cells responsible for minimal residual disease, and variable patient responses. Resistance mechanisms are heterogeneous, involving both *BCR-ABL1*-dependent (e.g., kinase domain mutations) and -independent (e.g., activation of alternative survival pathways) factors.  To address these challenges, a deeper understanding of the CML signaling network and its evolution under therapeutic pressure is essential. Furthermore, there is a critical need for robust biomarkers beyond *BCR-ABL1* transcript levels. Such biomarkers could stratify risk at diagnosis, predict TKI response and resistance, detect early signs of progression, and guide personalized therapeutic strategies. Potential candidates include specific kinase domain mutations, inflammatory cytokines (e.g., IL-6, TGF-β), microRNAs, metabolic markers, and proteins within the key dysregulated pathways.  This review provides a comprehensive overview of the major molecular signaling pathways implicated in CML pathogenesis and progression. It further explores and evaluates emerging biomarkers—from genetic and proteomic to metabolic and inflammatory profiles—with the potential to enhance clinical decision-making, improve patient outcomes, and inform the development of novel therapeutic approaches.

Keywords: Chronic myeloid leukemia; BCR–ABL1; signalling pathways; biomarkers; tyrosine kinase inhibitors; precision medicine

1. Introduction

Chronic Myeloid Leukemia (CML) is a paradigm-shifting malignancy in oncology, serving as a model for understanding the molecular basis of cancer and the development of targeted therapy. It is a myeloproliferative neoplasm arising from the genetic transformation of a hematopoietic stem cell, most definitively characterized by the Philadelphia (Ph) chromosome. This aberrant chromosome results from a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), which fuses the BCR (Breakpoint Cluster Region) gene with the ABL1 (Abelson tyrosine kinase 1) gene [1-10]. The resulting *BCR-ABL1* fusion gene is transcribed and translated into the BCR-ABL1 oncoprotein, a constitutively active tyrosine kinase that resides in the cytoplasm. Unlike its tightly regulated cellular counterpart, c-ABL, BCR-ABL1 operates independently of external growth factor signals, fundamentally corrupting the intracellular signaling machinery that governs normal hematopoiesis [2]. Clinically, CML manifests in a triphasic trajectory: an initial, relatively indolent chronic phase marked by granulocytic expansion; an intermediate accelerated phase of increasing cellular atypia and treatment resistance; and a terminal blast crisis, which resembles an acute leukemia characterized by genetic chaos and therapeutic refractoriness [3]. This progression mirrors the accrual of additional genetic and epigenetic lesions beyond *BCR-ABL1* itself.   

While the discovery of BCR-ABL1 established a singular oncogenic driver, contemporary research underscores that CML is a disease of intricate signaling networks. BCR-ABL1 acts not as a solitary actor but as a master regulator, initiating a cascade of interconnected pathways that dysregulate core cellular processes: proliferation, apoptosis, adhesion, differentiation, and metabolism. The clinical success of tyrosine kinase inhibitors (TKIs) validated BCR-ABL1 as a therapeutic target, yet also revealed the complexity of the disease, as resistance and relapse remain significant hurdles. Consequently, the scientific focus has expanded beyond the primary oncogene to map its downstream signaling ecosystem and to identify the vulnerabilities within it. This has propelled the search for biomarkers—objective, measurable indicators of biological or pathogenic processes. Advances in genomics, transcriptomics, and proteomics are now yielding a new generation of biomarkers that refine diagnosis beyond cytogenetics, predict prognosis and TKI response with greater accuracy, enable sensitive monitoring of minimal residual disease (MRD), and identify novel targets for combinatorial therapies [4,11-25]. This review details the major signaling pathways (Figure 1) co-opted by BCR-ABL1 and examines the emerging biomarkers that are translating this molecular understanding into clinical practice.

Figure 1. Schematic overview of key signaling pathways and biomarkers in chronic myeloid leukemia (CML). This diagram illustrates the central role of the BCR-ABL1 oncoprotein in CML pathogenesis. The constitutively active BCR-ABL1 tyrosine kinase (center) activates a network of downstream signaling pathways (PI3K/AKT/mTOR, JAK/STAT, MAPK/ERK, NF-κB) that promote leukemic cell survival, proliferation, and resistance to apoptosis. It also influences key stem cell regulatory pathways (Wnt/β-catenin, Hedgehog). The figure integrates diagnostic, prognostic, and emerging biomarkers circulating in the periphery, highlighting the transition from the chronic phase to the advanced accelerated/blast phase, driven by genomic instability and clonal evolution. Key therapeutic agents (TKIs) and potential combinatorial targets are indicated. Abbreviations: TKI, tyrosine kinase inhibitor; LSC, leukemic stem cell; ECM, extracellular matrix; miRNA, microRNA; lncRNA, long non-coding RNA.

2. BCR–ABL1 signalling axis in CML

The BCR-ABL1 oncoprotein is the engine of CML pathogenesis, and its constitutive tyrosine kinase activity is the primary source of pathologic signaling. Structurally, the fusion confers dimerization domains from BCR that promote oligomerization and autophosphorylation, leading to the permanent “on” state of the ABL1 kinase domain. This deregulated activity phosphorylates a vast array of downstream substrates, effectively hijacking normal cytokine receptor signaling pathways to operate in a ligand-independent manner [5]. The consequences are multifaceted: it drives uncontrolled proliferation through pathways like RAS/MAPK, confers a profound survival advantage by inhibiting apoptosis via PI3K/AKT and STAT5, and disrupts the cytoskeletal architecture, leading to defective adhesion of leukemic cells to the bone marrow stroma [26-37]. This adhesion defect is critical, as it causes premature release of immature myeloid cells into the peripheral blood and may also contribute to the aberrant mobilization and survival of leukemic stem cells.

Furthermore, BCR-ABL1 activity is genotoxic. It induces oxidative stress and interferes with DNA repair mechanisms, leading to an increased rate of DNA double-strand breaks. This creates a state of genomic instability that is a hallmark of cancer progression [6]. While the chronic phase is maintained by BCR-ABL1 alone, this underlying genetic fragility sets the stage for the acquisition of additional mutations (e.g., in TP53, RB1, MYC, or ASXL1). These secondary hits are the catalysts for clonal evolution, driving the transition to the more aggressive accelerated and blast crisis phases. This genomic instability also underpins one major mechanism of TKI resistance: the selection of leukemic clones harboring point mutations within the BCR-ABL1 kinase domain (e.g., T315I) that impair drug binding while preserving oncogenic activity.

3. Major signalling pathways in CML

3.1 PI3K/AKT/mTOR pathway

The PI3K/AKT/mTOR axis is a central signaling node for cell survival, growth, and metabolic adaptation. BCR-ABL1 directly activates PI3K, leading to the generation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) at the membrane. This recruits and activates AKT (Protein Kinase B), which in turn phosphorylates numerous targets. A key downstream effector is the mechanistic target of rapamycin (mTOR), which exists in two complexes (mTORC1 and mTORC2). mTORC1 activation drives protein synthesis, lipid biosynthesis, and inhibits autophagy, providing the anabolic foundation for rapid cell proliferation. Crucially, AKT phosphorylates and inactivates pro-apoptotic proteins like BAD and FOXO transcription factors, thereby shutting down a major cell death program [7]. The pathway’s role in CML extends to therapy resistance and stem cell maintenance. Leukemic stem cells (LSCs) demonstrate a dependency on PI3K signaling for their survival, and its persistent activation, even in the presence of TKIs, contributes to the persistence of minimal residual disease. Consequently, combining TKIs with PI3K or mTOR inhibitors is an active area of preclinical and clinical investigation aimed at eradicating the therapy-resistant stem cell pool [8].

3.2 MAPK/ERK pathway

The Mitogen-Activated Protein Kinase (MAPK) pathway, with its core RAF-MEK-ERK cascade, is a classic mitogenic signaling route. BCR-ABL1 activates this pathway primarily through adaptor proteins like GRB2, which engage with the guanine nucleotide exchange factor SOS to convert the small GTPase RAS into its active, GTP-bound form. Active RAS then triggers a phosphorylation cascade: RAF phosphorylates MEK, which in turn phosphorylates ERK. Activated ERK translocates to the nucleus, where it phosphorylates transcription factors such as ELK1 and c-MYC, driving the expression of genes that promote cell cycle progression from G1 to S phase [9]. While essential for the proliferative signal in chronic phase CML, dysregulated MAPK/ERK signaling becomes increasingly prominent during disease progression. In blast crisis, hyperactivation or mutations within this pathway can provide a BCR-ABL1-independent growth signal, contributing to therapeutic resistance and aggressive disease biology [10, 1-5, 37-43].

3.3 JAK/STAT pathway

The JAK/STAT pathway is the principal signaling conduit for hematopoietic cytokines like erythropoietin and interleukin-3. Normally, cytokine binding induces JAK kinase activation and subsequent phosphorylation of STAT proteins, which dimerize and translocate to the nucleus to regulate gene expression. BCR-ABL1 short-circuits this extracellular requirement by directly phosphorylating and activating STAT5, a particularly critical STAT family member in CML. Constitutively active STAT5 dimers drive the transcription of a battery of genes that enforce cell survival and proliferation. Key among its targets are the anti-apoptotic proteins BCL-XL and MCL-1, which neutralize the intrinsic apoptotic pathway [11]. Beyond acute survival, STAT5 activation is intrinsically linked to the maintenance and self-renewal of leukemic stem cells. Its persistent signaling, even under TKI pressure, helps maintain the LSC compartment. High levels of phospho-STAT5 have been correlated with poorer prognosis and are considered a potential biomarker of aggressive disease and stem cell persistence [12].

3.4 NF-κB pathway

The Nuclear Factor kappa B (NF-κB) family of transcription factors are master regulators of the immune response, inflammation, and cell survival. In unstimulated cells, NF-κB is sequestered in the cytoplasm by inhibitor of κB (IκB) proteins. BCR-ABL1 activates the IκB kinase (IKK) complex, leading to IκB phosphorylation, ubiquitination, and degradation [1-10]. This liberates NF-κB dimers (commonly p50/RelA) to enter the nucleus and activate gene expression. In CML, NF-κB upregulates a suite of anti-apoptotic genes (e.g., *BFL-1*, cIAP2), cell cycle regulators, and inflammatory cytokines, creating a pro-survival and pro-proliferative transcriptional landscape [13]. The pathway’s activation contributes significantly to TKI resistance, as it provides an alternative survival signal that can bypass BCR-ABL1 inhibition. Furthermore, NF-κB-mediated production of inflammatory cytokines can create a tumor-promoting microenvironment in the bone marrow, fostering disease progression [14].

3.5 Wnt/β-Catenin pathway

The Wnt/β-catenin pathway is a cornerstone of stem cell biology, governing self-renewal, fate decisions, and tissue homeostasis [44-50]. In the canonical pathway, Wnt ligand binding stabilizes β-catenin, allowing it to accumulate in the cytoplasm and translocate to the nucleus, where it partners with TCF/LEF transcription factors to activate target genes. In normal hematopoiesis, this pathway is tightly controlled. In CML, however, BCR-ABL1 can enhance β-catenin stability and nuclear accumulation through mechanisms involving GSK-3β inhibition. This aberrant activation is particularly pronounced and functionally critical within the leukemic stem cell compartment [15]. Active β-catenin signaling reinforces the self-renewal potential of LSCs, impairs their differentiation, and enhances their resistance to apoptosis induced by TKIs and other stresses. Its activity is a key factor in the persistence of LSCs during therapy and is strongly implicated in disease relapse, making it a prime target for strategies aimed at curative eradication of the disease [16].

3.6 Hedgehog Signalling

The Hedgehog (Hh) pathway, vital for embryonic patterning, also plays a role in maintaining adult stem cell niches [1-3]. Its activation involves ligand binding to the Patched receptor, relieving its inhibition of Smoothened, which then triggers the activation of GLI transcription factors. In CML, evidence suggests aberrant activation of Hh signaling, potentially through BCR-ABL1-mediated upregulation of GLI1. This pathway contributes to the maintenance and survival of leukemic stem cells, promoting their quiescence and protection from cytotoxic therapies [17]. Pharmacological inhibition of Smoothened (e.g., with vismodegib or sonidegib) in combination with TKIs has demonstrated efficacy in preclinical models, reducing the LSC burden and delaying relapse, highlighting its therapeutic potential as an adjunct to standard therapy [18].

3.7 TGF-β and notch pathways

The Transforming Growth Factor-beta (TGF-β) and Notch pathways are pivotal regulators of hematopoietic stem cell (HSC) quiescence, differentiation, and niche interaction. TGF-β typically acts as a potent inhibitor of HSC proliferation, enforcing a quiescent state. In CML, this regulatory brake is often impaired; leukemic stem cells can exhibit decreased sensitivity to TGF-β’s growth-inhibitory signals, allowing for inappropriate proliferation. Conversely, some evidence suggests TGF-β signaling may be co-opted to promote fibrosis or immune suppression in the microenvironment. The Notch pathway, involved in cell fate decisions, also displays dysregulation in CML. Altered Notch signaling can contribute to skewed differentiation, impaired HSC function, and the survival advantage of leukemic clones [19]. The complex, sometimes paradoxical roles of these pathways in CML—balancing between tumor-suppressive and tumor-promoting effects—are areas of active investigation, as they represent additional layers of regulation in the leukemic stem cell niche that could be therapeutically exploited.

4. Biomarkers in CML

4.1 Diagnostic biomarkers

The definitive diagnosis of Chronic Myeloid Leukemia is a multi-modal process anchored in the objective detection of the *BCR-ABL1* fusion gene, a molecular lesion pathognomonic for the disease. Clinical suspicion is typically triggered by a routine complete blood count revealing a sustained, marked leukocytosis characterized by a full spectrum of granulocytic precursors (myelocytes, metamyelocytes) in the peripheral blood—a “granulocytic left shift”—often accompanied by basophilia, eosinophilia, and thrombocytosis or thrombocytopenia. However, confirmation necessitates specialized laboratory investigations. The historical and still fundamental diagnostic test is the visualization of the Philadelphia (Ph) chromosome via conventional karyotyping of bone marrow metaphase cells. This technique not only confirms the t(9;22) translocation but provides a critical global view of the genome. It remains indispensable for identifying Additional Cytogenetic Abnormalities (ACAs) in Ph+ cells, such as trisomy 8, isochromosome 17q, or a second Ph chromosome. The emergence of these ACAs, a process termed clonal evolution, is a cardinal feature of genetic instability and is formally integrated into the diagnostic criteria for accelerated phase disease, making karyotyping a vital tool for staging and risk assessment at diagnosis and during follow-up [21, 51-60]. 

The cornerstone of modern molecular diagnostics is quantitative reverse transcription polymerase chain reaction (qRT-PCR) for the *BCR-ABL1* messenger RNA transcript. This highly sensitive and specific technique is the gold standard, capable of detecting one leukemic cell among 100,000 normal cells. It serves three crucial diagnostic functions: 1) Confirmatory, by definitively proving the presence of the fusion gene; 2) Characterizing, by identifying the specific breakpoint type (e.g., the major M-BCR transcripts b2a2 and b3a2, or the minor m-BCR transcript e1a2), with the rare e1a2 variant associated with a more aggressive phenotype; and 3) Quantitative, by establishing the baseline transcript level expressed on the International Scale (IS), which is essential for all subsequent molecular monitoring. A complementary technique, fluorescence in situ hybridization (FISH), uses fluorescent DNA probes to visualize the *BCR-ABL1* fusion at the chromosomal level in both dividing (metaphase) and non-dividing (interphase) cells. FISH is particularly valuable for diagnosing cases with variant or complex translocations involving other chromosomes, for analyzing samples with low mitotic yield, and for confirming the presence of the fusion in ambiguous cases. The integrated use of karyotyping, FISH, and qRT-PCR at diagnosis ensures a comprehensive genetic profile, establishing an unequivocal diagnosis, assessing baseline risk, and providing the essential benchmark for evaluating therapeutic efficacy.

4.2 Prognostic biomarkers

Effective management of CML requires accurate prognostication to stratify patients at diagnosis and guide therapeutic intensity. Prognostic biomarkers estimate the natural history of the disease and the probability of responding to standard therapy. The foundation of clinical risk stratification rests on composite scoring systems: the Sokal score (derived in the chemotherapy era) and the Hasford (or Euro) score (developed in the early interferon era). These scores integrate readily available clinical and hematologic parameters—patient age, spleen size, platelet count, and percentages of blasts, basophils, and eosinophils—to categorize patients into low-, intermediate-, and high-risk groups. Despite the advent of TKIs, these scores retain clinical utility, particularly for selecting a first-line TKI, as high-risk patients may benefit from upfront treatment with more potent second-generation agents.  With TKI therapy, molecular monitoring itself has become the most powerful dynamic prognostic tool. The BCR-ABL1 transcript level at specific early time points is a robust surrogate for long-term outcomes. Failure to achieve an Early Molecular Response (EMR), defined as BCR-ABL1 IS ≤10% at 3 months, is a strong independent predictor of significantly higher risks of disease progression, failure to achieve later deep molecular responses, and inferior event-free and overall survival. Similarly, transcript levels >1% IS at 6 months define a suboptimal response, triggering clinical review. The most critical mutation-specific prognostic biomarkers are BCR-ABL1 kinase domain mutations, identified by Sanger or next-generation sequencing upon treatment failure or progression. Specific mutations confer varying degrees of resistance: the T315I “gatekeeper” mutation confers high-level resistance to all first- and second-generation TKIs, while mutations in the P-loop (e.g., Y253H, E255K/V) are associated with a poorer prognosis and resistance to imatinib and, to a lesser extent, other agents [23]. Beyond the oncogene itself, research is uncovering prognostic somatic mutations in other genes. Lesions in ASXL1, RUNX1, IKZF1, TP53, and TET2, often acquired during clonal evolution, are associated with disease progression to blast crisis and a poorer overall prognosis. Their detection, especially at diagnosis or during routine monitoring, may help identify patients with intrinsically more aggressive disease biology.

4.3 Predictive biomarkers for therapy response

While prognostic biomarkers estimate overall outcome, predictive biomarkers forecast response to a specific therapeutic intervention, enabling truly personalized treatment selection. The most clinically actionable predictive biomarker is the Early Molecular Response (EMR) at 3 months. Achieving BCR-ABL1 IS ≤10% not only prognosticates well but also predicts a high likelihood of success with continuation of the current TKI regimen. Conversely, failure to achieve EMR predicts a high probability of suboptimal long-term outcomes with the current therapy, prompting consideration of early intervention such as switching to an alternative TKI [24]. 

Pharmacogenomic factors influencing drug metabolism and cellular uptake also serve as predictive biomarkers. For patients prescribed imatinib, the intrinsic activity of the Organic Cation Transporter 1 (OCT-1) is a key determinant of intracellular drug concentration. Patients with low OCT-1 activity exhibit significantly lower rates of major molecular response with standard-dose imatinib, suggesting they may be better candidates for upfront treatment with a higher imatinib dose or a different TKI with an OCT-1-independent uptake mechanism. At the molecular level, specific microRNA (miRNA) signatures are emerging as predictors of therapeutic response. For example, the downregulation of miR-203, which is frequently silenced by promoter hypermethylation induced by BCR-ABL1, is associated with enhanced oncogenic signaling and TKI resistance. Similarly, low levels of miR-150 correlate with disease aggressiveness and poorer response. Profiling these miRNAs at diagnosis could help identify patients with a molecular profile predisposing to suboptimal response, flagging them for more intensive monitoring or alternative therapeutic strategies from the outset.

4.4 Emerging biomarkers

The next frontier in CML biomarker discovery leverages advanced omics technologies to probe deeper into the biology of treatment resistance and leukemic stem cell (LSC) persistence. Circulating nucleic acids represent a paradigm shift toward non-invasive “liquid biopsy.” Profiles of circulating microRNAs and long non-coding RNAs (lncRNAs) in plasma or within exosomes (small extracellular vesicles) can reflect the tumor’s molecular state. Specific signatures may provide an early warning of developing resistance or indicate the presence of a quiescent LSC compartment long before a rise in BCR-ABL1 transcript levels occurs.  Epigenetic biomarkers are gaining prominence as drivers of CML pathogenesis. Genome-wide analyses of DNA methylation have identified hypermethylation of specific gene promoters (e.g., of ABL1 or p15INK4b) associated with progression. Similarly, specific patterns of histone modifications (e.g., H3K27me3, H3K9ac) can indicate dysregulated gene expression programs that sustain LSCs. These epigenetic marks are potentially reversible, making them both biomarkers of high-risk disease and attractive therapeutic targets. Metabolic reprogramming is a hallmark of cancer, and CML is no exception. Metabolomic profiling can reveal shifts in glycolysis, oxidative phosphorylation, and amino acid metabolism induced by BCR-ABL1 and adapted under TKI pressure. Specific metabolic signatures could serve as functional biomarkers, signaling the activation of survival pathways (like PI3K/AKT) that sustain cells despite effective BCR-ABL1 inhibition [26]. 

Finally, advanced proteomic and phosphoproteomic profiling moves beyond static genetic lesions to capture the dynamic, functional state of signaling networks. By quantifying the activation status of thousands of proteins and phosphorylation sites, these technologies can identify which pathways (e.g., persistent JAK/STAT or PI3K/AKT signaling via p-STAT5 or p-AKT) remain active in a patient’s leukemic cells during TKI therapy. This “pathway activation mapping” provides a direct functional readout that could guide the selection of rational combination therapies, matching a patient’s active signaling network with a specific TKI plus a complementary pathway inhibitor [27]. The integration of these genomic, transcriptomic, epigenomic, metabolomic, and proteomic datasets—a true multi-omics approach—aims to construct a holistic, real-time molecular portrait of an individual’s leukemia, paving the way for predictive models that can precisely guide therapy from diagnosis through the challenge of treatment-free remission.

5. Clinical implications and therapeutic targeting

The direct translation of pathogenetic knowledge into therapy is exemplified by the development of tyrosine kinase inhibitors (TKIs). Imatinib, the first-generation TKI, revolutionized CML care. Second-generation agents (dasatinib, nilotinib, bosutinib) offer increased potency and activity against many imatinib-resistant mutations, and are often used as first-line therapies for high-risk patients. The third-generation TKI ponatinib was specifically designed to overcome the recalcitrant T315I mutation. Despite this powerful arsenal, several challenges persist. Leukemic stem cells (LSCs) are largely quiescent and survive TKI therapy through BCR-ABL1-independent mechanisms, serving as a reservoir for relapse. Furthermore, the activation of alternative signaling pathways (e.g., PI3K, JAK/STAT) provides bypass tracks that sustain cell survival even with effective BCR-ABL1 inhibition.

This understanding has shifted the therapeutic paradigm from sequential TKI monotherapy towards investigating rational combination therapies. Preclinical and early clinical studies are exploring TKIs combined with inhibitors of key ancillary pathways: PI3K/mTOR inhibitors to target survival signals, JAK2/STAT5 inhibitors to disrupt a critical LSC maintenance axis, Hedgehog pathway inhibitors to eradicate stem cells, and Wnt/β-catenin disruptors to impair LSC self-renewal [29]. The success of such strategies will heavily depend on biomarker-driven patient selection. Identifying patients with specific pathway activation (e.g., high p-STAT5) or a high-risk stem cell signature will be essential to match them with the appropriate combination, maximizing efficacy while minimizing toxicity. This approach embodies the core principle of precision oncology.

6. Future perspectives

The future of CML management lies in integrative multi-omics—the combined analysis of genomic, transcriptomic, epigenomic, proteomic, and metabolomic data from individual patients [1-10, 45-60]. This will enable the construction of a comprehensive molecular portrait of the disease, revealing novel vulnerabilities. Single-cell sequencing technologies will be transformative, dissecting the profound heterogeneity within the leukemic population, particularly the rare LSC compartment, and identifying the specific subclones responsible for resistance. Machine learning and systems biology approaches will be required to model this complex data, generating predictive algorithms for treatment response and relapse risk that far surpass current clinical scores.

Therapeutically, the most promising frontier remains the eradication of leukemic stem cells, the ultimate barrier to a cure. This will likely require combinations that simultaneously target BCR-ABL1, key survival pathways within the LSC, and their protective bone marrow microenvironment. Strategies may include TKIs with immune-modulating agents, epigenetic drugs, or therapies that disrupt the niche interactions that shelter LSCs [31]. The goal will shift from durable treatment-free remission to true molecular cure.

7. Conclusion

Chronic Myeloid Leukemia represents a landmark achievement in modern oncology, transforming from a universally fatal diagnosis into a paradigm for the power of molecularly targeted therapy. This therapeutic revolution is rooted in a profound and progressively detailed understanding of the disease’s pathogenesis. At its core lies the BCR-ABL1 oncoprotein, a constitutively active tyrosine kinase that functions as a master regulator, corrupting the fundamental signaling architecture of the hematopoietic stem cell. It does not act in isolation but rather orchestrates a vast, interconnected network of intracellular pathways. The PI3K/AKT/mTOR axis is hijacked to enforce cell survival and anabolic growth; the MAPK/ERK cascade is commandeered to drive uncontrolled proliferation; the JAK/STAT pathway, particularly STAT5, is activated to transcribe a program of anti-apoptotic defense. Furthermore, BCR-ABL1 co-opts critical developmental and stress-response pathways—including NF-κB, Wnt/β-catenin, and Hedgehog—that are essential for maintaining the leukemic stem cell compartment and fostering a permissive bone marrow microenvironment. This intricate signaling ecosystem is not static; it evolves under the selective pressure of tyrosine kinase inhibitor (TKI) therapy, with the adaptive upregulation or dependency shift of these ancillary pathways forming a primary basis for acquired treatment resistance and disease progression. 

The clinical management of CML has been equally revolutionized by the parallel development of sophisticated biomarkers, creating a framework for precision medicine. The journey begins with the diagnostic gold standard of quantifying the *BCR-ABL1* transcript, but extends far beyond mere detection. Prognostic stratification now incorporates dynamic molecular responses, where early transcript reduction powerfully predicts long-term outcomes, and the detection of BCR-ABL1 kinase domain mutations provides a direct molecular explanation for therapeutic failure. The future lies in the integration of emerging multi-omics biomarkers—from epigenetic signatures and microRNA profiles to metabolomic and proteomic readouts—which promise to unveil the functional state of the leukemic cell and its supportive niche. This will enable a shift from reactive to pre-emptive management, allowing clinicians to identify patients at high risk of resistance or relapse before clinical signs emerge and to select rational, biomarker-driven combination therapies. 

Despite these extraordinary advances, the quest for a cure for all patients continues. The most formidable remaining obstacle is the persistent leukemic stem cell (LSC), a quiescent, drug-tolerant reservoir that evades BCR-ABL1 inhibition through both intrinsic plasticity and protective niche interactions. Eradicating these cells requires moving beyond BCR-ABL1-centric therapy. Future research must therefore relentlessly focus on dissecting the unique biology of LSCs and the signaling ecosystem that sustains them, identifying novel vulnerabilities within pathways like Wnt/β-catenin and Hedgehog, or targeting the immune and stromal components of the bone marrow microenvironment. Combining this biological insight with advanced technologies—such as single-cell analytics and AI-driven predictive modeling—will be crucial. In conclusion, CML stands as a testament to the success of translational research, where discoveries at the bench have been directly applied at the bedside. By building on this foundation and targeting the final frontiers of stem cell persistence and clonal evolution, the ultimate goal of achieving durable, treatment-free remission—and true cure—for every CML patient moves firmly within reach.

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

Funding: Not applicable.

Acknowledgments: We are grateful to the Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 22233, Saudi Arabia 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: We have already mentioned in details in the method section.

Informed Consent Statement: We have already mentioned in details in the method section.

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

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