Bone marrow niche adaptation, leukemic stem cell persistence, and therapeutic resistance in FLT3-mutated leukemia

Abstract

FLT3 mutations, especially FLT3-internal tandem duplication and FLT3-tyrosine kinase domain mutations, are among the most common genetic lesions in acute myeloid leukemia (AML) and are closely associated with aggressive disease biology, early relapse, and poor survival. Although FLT3 inhibitors have improved outcomes in both newly diagnosed and relapsed/refractory AML, durable remission remains limited by adaptive resistance and the persistence of leukemia stem cells. Increasing evidence indicates that treatment failure in FLT3-mutated AML is not determined solely by secondary kinase mutations, but also by dynamic interactions between leukemic cells and the bone marrow microenvironment (BMM). The BMM provides structural support, soluble mediators, metabolic substrates, and immune protection, thereby preserving a therapy-tolerant leukemic reservoir. This review summarizes the molecular features of FLT3 mutations, the bidirectional crosstalk between FLT3-mutated leukemia cells and the BMM, the formation of leukemia stem cell-supportive niches, and the principal mechanisms of microenvironment-mediated resistance, including adhesion signaling, chemokine retention, bypass pathway activation, autophagy, metabolic adaptation, and immune evasion. It also discusses emerging combination strategies aimed at cotargeting FLT3 signaling, the supportive niche, and stem-cell-specific vulnerabilities.

Key Words: FLT3 mutation; Acute myeloid leukemia; Bone marrow microenvironment; Leukemia stem cell; Therapeutic resistance

Core Tip: FLT3-mutated leukemia remains clinically challenging because therapeutic resistance is driven not only by intrinsic oncogenic signaling, but also by adaptive interactions with the bone marrow microenvironment. This review highlights how stromal protection, chemokine-mediated retention, hypoxic support, metabolic rewiring, immune evasion, and leukemia stem cell persistence collectively promote treatment failure and relapse. It also summarizes current and emerging therapeutic strategies aimed at cotargeting FLT3 signaling, the supportive niche, and stem cell-related vulnerabilities.

INTRODUCTION

FLT3 mutations are the most common recurrent molecular abnormalities in acute myeloid leukemia (AML) and are detected in approximately 25%-30% of newly diagnosed patients[1,2]. FLT3-internal tandem duplication (FLT3-ITD) is the predominant subtype and is strongly associated with high leukemic burden, increased relapse risk, and inferior overall survival[1,3,4]. FLT3-tyrosine kinase domain (FLT3-TKD) mutations are less frequent than FLT3-ITD mutations and usually involve point mutations in the kinase domain, most commonly at D835[2,3]. Although the prognostic effect of FLT3-TKD is more heterogeneous, it also contributes to constitutive FLT3 activation and disease progression[2,5].

The introduction of FLT3 tyrosine kinase inhibitors (TKIs), such as midostaurin, gilteritinib, and quizartinib, has significantly changed the treatment landscape of FLT3-mutated AML[2-4]. Midostaurin combined with standard chemotherapy improved survival in newly diagnosed FLT3-mutated AML and established FLT3 as a clinically actionable target[3]. More selective second-generation inhibitors, including gilteritinib and quizartinib, further expanded targeted treatment options in relapsed or refractory disease[1,4]. However, despite these advances, many patients ultimately relapse or fail to achieve durable remission[6,7].

A major reason for this limitation is that FLT3-mutated AML is not sustained by intrinsic kinase activation alone[6,8]. Leukemic cells reside within a highly specialized bone marrow microenvironment (BMM) composed of mesenchymal stromal cells, endothelial cells, osteoblasts, adipocytes, immune cells, extracellular matrix, cytokines, and chemokines[7,9]. This microenvironment is progressively remodeled by leukemia cells into a pathological niche that protects blasts and leukemia stem cells (LSCs) from chemotherapy and targeted agents[7,10]. As a result, resistance to FLT3 inhibition often reflects not only on-target FLT3 mutations, but also microenvironment-mediated adaptive mechanisms, including activation of alternative survival signaling, induction of autophagy, metabolic rewiring, immune suppression, and maintenance of a quiescent LSC pool[6,8,11]. Accordingly, understanding how FLT3-mutated leukemia cells adapt to and exploit the BMM is essential for designing therapies capable of producing deeper and more durable remissions. Unlike previous reviews that mainly discuss FLT3-targeted therapies, LSCs, or the bone marrow microenvironment separately, the present review integrates these aspects and focuses on how bone marrow niche adaptation drives LSC persistence and therapeutic resistance in FLT3-mutated AML. In addition, we discuss emerging therapeutic strategies aimed at simultaneously targeting FLT3 signaling, the supportive niche, and stem cell-related vulnerabilities[7,12].

BIOLOGICAL CHARACTERISTICS OF FLT3 MUTATIONS IN AML

FLT3 is a class III receptor tyrosine kinase that plays a key role in normal hematopoiesis by regulating the survival, proliferation, and differentiation of hematopoietic stem and progenitor cells[2]. Under physiological conditions, FLT3 activation is ligand dependent and tightly controlled[2]. Structurally, FLT3 contains an extracellular ligand-binding domain, a transmembrane domain, a juxtamembrane domain with autoinhibitory function, and an intracellular tyrosine kinase domain[13]. This structural organization allows FLT3 to transmit tightly regulated developmental signals within the marrow niche[2,13].

FLT3-ITD mutations account for the majority of FLT3 alterations in AML[2]. These mutations occur mainly in the juxtamembrane domain and disrupt its inhibitory function, resulting in constitutive ligand-independent receptor activation[2]. Persistent FLT3-ITD signaling activates signal transduction activator of transcription 5 (STAT5), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase/protein kinase B pathways, thereby promoting leukemic proliferation, survival, and apoptosis resistance[1,2]. Clinically, FLT3-ITD is strongly associated with high leukemic burden, early relapse, and poor survival, making it a major prognostic marker and therapeutic target[3,4].

FLT3-TKD mutations represent another activating subtype and usually involve point mutations within the kinase domain, especially at D835[2,5]. These lesions also induce constitutive receptor activation, but may display distinct downstream signaling profiles and different sensitivity patterns to FLT3 inhibitors compared with FLT3-ITD[2,5]. Their clinical significance is generally considered less consistent than that of FLT3-ITD[3].

FLT3 mutations are major drivers of leukemia initiation and progression in AML[1,3]. Constitutive activation of FLT3 results in persistent stimulation of proliferative and prosurvival pathways such as STAT5, phosphatidylinositol 3-kinase/protein kinase B, and MAPK/extracellular signal-regulated kinase (ERK), thereby fueling leukemic expansion[2,14]. These downstream programs enhance blast proliferation, suppress apoptosis, and promote aggressive disease behavior[15,16]. Importantly, FLT3 signaling also contributes to LSC maintenance and therapeutic resistance[17]. FLT3-ITD-positive primitive leukemic compartments exhibit enhanced self-renewal capacity and use multiple mechanisms to evade therapy, including acquisition of secondary kinase-domain mutations, activation of parallel survival pathways, and protection by the bone marrow niche[8,18,19]. This helps explain why FLT3-mutated AML frequently relapses despite initial response[4,17].

FLT3 mutations also frequently cooperate with other molecular lesions, especially DNMT3A and NPM1 alterations[20,21]. Such combinations may amplify leukemogenesis, enhance stemness-related programs, and further worsen prognosis[20]. Therefore, FLT3-mutated AML is best understood as a biologically layered disease in which oncogenic kinase activation interacts with cooperating mutations and niche-dependent survival mechanisms[16,22].

CLINICAL APPLICATION AND LIMITATIONS OF FLT3 INHIBITORS

FLT3 inhibitors have become integral to the treatment of FLT3-mutated AML[3,4]. Midostaurin is used in combination with standard induction and consolidation chemotherapy for newly diagnosed FLT3-mutated AML and established proof of principle for FLT3-targeted therapy in the frontline setting[3]. Gilteritinib and quizartinib, which are more potent and selective inhibitors, are widely used in relapsed or refractory FLT3-mutated AML[1,4]. Quizartinib has also entered frontline combination strategies for newly diagnosed FLT3-ITD-positive AML in some regions[4].

Despite these advances, FLT3 inhibitor therapy remains limited by frequent development of resistance[6,11,18]. One important mechanism is the acquisition of secondary on-target mutations within the FLT3 kinase domain, such as D835Y and F691 L, which reduce inhibitor sensitivity[11,18]. Another mechanism is off-target activation of alternative survival pathways, including RAS/MAPK and JAK/STAT signaling, which allows leukemic cells to maintain growth despite FLT3 blockade[6,11,18]. In addition, the bone marrow microenvironment contributes to adaptive resistance through multiple protective mechanisms, which are discussed in detail below[8,11,18].

Another major limitation is the inability of FLT3 inhibitors to fully eradicate LSCs[6,7,17]. A residual stem-like compartment can survive in protected marrow niches and later regenerate disease[7,17]. This is clinically relevant even after allogeneic hematopoietic cell transplantation, as relapse remains common in FLT3-ITD AML despite transplant-based consolidation[4,23,24]. For this reason, post-transplant FLT3 inhibitor maintenance has emerged as an important strategy, although the optimal agent, timing, and duration remain under investigation[23-25].

Several approaches are being developed to address these limitations[19,26]. One strategy is the development of next-generation inhibitors active against resistant FLT3 variants, such as irreversible inhibitors like FF-10101 or multitarget agents such as foretinib[25,26]. Another strategy is rational combination therapy, including FLT3 inhibitors with BCL-2 inhibitors, hypomethylating agents, or inhibitors of bypass pathways such as ERK signaling[22,27-29]. Additional approaches include FLT3 protein degradation, bispecific antibodies, and FLT3-directed cellular immunotherapies[19,30].

BIDIRECTIONAL COMMUNICATION BETWEEN FLT3-MUTATED LEUKEMIA CELLS AND THE BMM

The BMM functions as a protective sanctuary for FLT3-mutated AML cells and substantially limits the efficacy of FLT3 inhibitors[31,32]. Bone marrow-derived conditioned media can preserve STAT3 and STAT5 activity and reduce the sensitivity of FLT3-ITD-positive cells to potent FLT3 inhibition, indicating that stromal protection can operate even when the oncogenic kinase is pharmacologically suppressed[31]. This early extrinsic protection is clinically relevant because it allows a fraction of leukemic cells to survive initial treatment and subsequently evolve into a more stable drug-resistant population[32]. Thus, resistance in FLT3-mutated AML is not solely a consequence of leukemia-intrinsic mutations, but also reflects a dynamic adaptation to niche-derived support[6,11,31,32].

A major feature of this adaptation is activation of compensatory signaling pathways (Figure 1). Cytokines and inflammatory mediators within the marrow niche can induce signaling modules that bypass FLT3 blockade and sustain leukemic cell survival[33-35]. Interferon gamma-dependent STAT1 activation has been implicated in resistance through induction of alternative receptor programs such as AXL[33]. Bone marrow stroma has been shown to activate BTK in FLT3-mutated AML, which promotes cytoprotective autophagy and weakens the antileukemic activity of FLT3 inhibitors[34]. In addition, microenvironmental hypoxia and cytokine exposure can stimulate kinases such as BMX, allowing persistent STAT5 phosphorylation independently of FLT3 signaling[35]. These observations indicate that the BMM is not simply a passive shelter, but an active signaling hub that broadens the survival repertoire of FLT3-mutated leukemia cells[31-35].

Figure 1 Schematic overview of bone marrow niche adaptation, leukemia stem cell persistence, and therapeutic resistance in FLT3-mutated acute myeloid leukemia. A: Mesenchymal stromal cells promote leukemic cell survival through adhesion-mediated protection and C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4-mediated retention; B: Endothelial and hypoxic niches support bypass signaling activation as well as leukemia stem cell quiescence and persistence; C: Immune-cell remodeling contributes to immunosuppression and immune evasion within the bone marrow microenvironment; D: Adipocytes and extracellular matrix provide metabolic support and promote microenvironment remodeling. Collectively, these microenvironmental adaptations support leukemia stem cell maintenance, therapeutic resistance, and disease relapse, while also providing potential targets for FLT3 inhibitors, venetoclax-based combinations, C-X-C chemokine receptor type 4 inhibition, autophagy targeting, metabolic intervention, post-transplant maintenance, and other niche-directed strategies. MSC: Mesenchymal stromal cell; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C chemokine receptor type 4; LSC: Leukemia stem cell; DC: Dendritic cell; MDSC: Myeloid-derived suppressor cell; TAM: Tumor-associated macrophages; ECM: Extracellular matrix; AML: Acute myeloid leukemia.

The BMM also induces profound metabolic and immune adaptation (Table 1). Under FLT3 inhibitor pressure, stromal support can preserve glycolytic activity and facilitate broader metabolic plasticity, thereby sustaining a slow-cycling, drug-tolerant leukemic state[31,32]. Hypoxia within the marrow has been associated with transcriptional programs related to stemness, stress tolerance, and treatment persistence in AML, and these mechanisms may also contribute to FLT3-mutated disease[30,36,37]. At the same time, FLT3-mutated leukemia remodels the immune milieu. FLT3-ITD can be retained in dendritic cells and disturb their homeostasis, with downstream effects on T-helper polarization[38]. It can also drive noncanonical STAT1 signaling and increase CD276 expression, thereby contributing to CD8+ T-cell exhaustion and impaired immune surveillance[39]. Through these combined signaling, metabolic, and immune mechanisms, FLT3-mutated leukemia establishes a supportive ecosystem that favors long-term persistence rather than immediate eradication[31-39].

Table 1 Key bone marrow microenvironment-mediated resistance mechanisms in FLT3-mutated acute myeloid leukemia.

Mechanism	Representative factors	Main consequence	Ref.
Adhesion-mediated protection	Stromal/endothelial contact, adhesion signaling	Enhances leukemic cell survival and niche retention	[18,29]
CXCL12/CXCR4-mediated retention	CXCL12, CXCR4	Promotes homing, persistence, and adaptive resistance	[64,65]
Soluble factor-mediated bypass signaling	FLT3 ligand, inflammatory cytokines	Reduces dependence on FLT3 signaling	[8,31]
Autophagy activation	Microenvironment-induced autophagy	Supports survival under FLT3 inhibitor pressure	[8,32]
Metabolic adaptation	Glycolysis, OXPHOS, lipid/amino acid metabolism	Maintains energy supply and stress tolerance	[31,60]
Hypoxic niche support	Hypoxia-related programs	Preserves quiescence and stem-like features	[36,37]
Immune remodeling	T-cell exhaustion, macrophage polarization	Favors immune evasion and residual disease survival	[35,39]

CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C chemokine receptor type 4.

BMM REMODELING AND LSC PERSISTENCE

The normal BMM is a highly organized tissue composed of mesenchymal stromal cells, endothelial cells, osteoblasts, adipocytes, extracellular matrix, and immune-cell populations that collectively regulate homing, quiescence, differentiation, and self-renewal of hematopoietic stem cells[9,10]. In AML, this architecture is progressively corrupted into a malignant niche that suppresses normal hematopoiesis and preferentially supports leukemic blasts and LSCs[7,9-12,40]. Leukemic cells actively reprogram stromal and vascular compartments, alter cytokine and chemokine networks, and reshape local metabolism, thereby creating a marrow environment that favors disease propagation and therapeutic resistance[10-12,40]. Elevated lactate in the AML marrow can further polarize macrophages toward immunosuppressive phenotypes, reinforcing leukemic progression and weakening host antitumor responses[39].

Mesenchymal stromal cells are central to this remodeling process (Figure 1). In AML, they may exhibit impaired osteogenic and adipogenic differentiation and can be converted into tumor-supportive fibroblast-like populations that enhance leukemic survival[41,42]. Leukemia-derived extracellular vesicles and exosomes further amplify this process by transferring regulatory molecules that alter surrounding stromal and hematopoietic cells[43,44]. The vascular niche is another critical component, as endothelial interactions promote adhesion, anti-apoptotic signaling, and post-chemotherapy persistence of leukemic cells[44]. Hypoxic niches also contribute by maintaining a low-proliferative, stress-tolerant state and activating hypoxia-related programs associated with stemness and drug resistance[36,37]. Together, these changes establish a remodeled marrow ecosystem in which leukemic cells are structurally protected, metabolically supported, and less susceptible to therapy[36,40-46].

This pathological niche is particularly important for LSC persistence. LSCs are defined by self-renewal capacity, disease-propagating potential, and relative resistance to cytotoxic and targeted therapies, and they are widely regarded as the cellular basis of relapse in AML[7,37,47]. In FLT3-mutated AML, LSC persistence is reinforced by both oncogenic signaling and niche-derived support[1,2,4,17]. FLT3-ITD promotes aggressive disease biology and contributes to survival of primitive leukemic compartments, but durable treatment failure arises in large part because these cells are maintained in protected marrow niches[2,17]. Adhesion molecules, chemokine gradients, endothelial interactions, hypoxia, autophagy, and metabolic rewiring collectively support LSC homing, retention, quiescence, and survival under therapy[8,36,45,47,48]. As a result, even when bulk blasts are substantially reduced, a residual stem-like reservoir may remain embedded in the marrow and later regenerate disease[47,49-52].

A hallmark of this process is quiescence. Many LSCs adopt a slow-cycling or dormant state that confers relative insensitivity to conventional chemotherapy, which mainly targets actively dividing cells[49,50]. The niche actively sustains this state through C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4)-mediated retention, hypoxic signaling, stromal contact, and anti-apoptotic support from vascular and mesenchymal compartments[36,37,45,47,49,50]. In parallel, adaptive processes such as autophagy and metabolic flexibility help LSCs tolerate nutrient limitation, oxidative stress, and drug exposure[8,36,48]. Therefore, LSC persistence in FLT3-mutated AML should be understood not simply as a property of an intrinsically resistant cell population, but as the outcome of continuous reciprocal interactions between primitive leukemic cells and a remodeled supportive niche[7-12,47,49-52].

MECHANISMS OF BMM-MEDIATED THERAPEUTIC RESISTANCE IN FLT3-MUTATED LEUKEMIA

Microenvironment-mediated resistance in FLT3-mutated AML is multifactorial and involves direct cellular contact, soluble mediators, metabolic adaptation, and immune evasion[8,12,28,53,54]. One major mechanism is cell adhesion-mediated drug resistance. Leukemic cells interact with stromal cells, endothelial cells, and extracellular matrix components, thereby receiving anti-apoptotic and prosurvival signals that diminish sensitivity to therapy[18,29,44,53]. Adhesion-dependent protection also promotes retention of leukemic cells within protective marrow sites and contributes to early therapeutic escape[18,29,53]. In FLT3-mutated AML, resistance-associated changes in cell migration and adhesion programs, including the leupaxin-PTK2B axis, further support the role of adhesion signaling in therapeutic failure[18]. Evidence from related myeloid leukemias further shows that quiescent stem-cell populations marked by specific surface phenotypes such as CD93 can persist after TKI therapy, supporting the broader concept that protected stem-like cells may survive within therapy-permissive niches[55]. Residual AML stem-cell populations with distinct phenotypic and prognostic characteristics have likewise been associated with relapse persistence and adverse outcome[56].

Extracellular matrix remodeling and laminin-associated signaling within the marrow niche also contribute to leukemic progression and regenerative adaptation[57]. In parallel, inflammatory niche remodeling has emerged as an important driver of tissue dysfunction and disease progression in AML[58]. Autophagy has emerged as one of the most important microenvironment-enabled resistance pathways in FLT3-ITD AML[8,32,59]. Signals derived from the BMM can induce cytoprotective autophagy, allowing leukemic cells to maintain downstream survival signaling and avoid apoptosis during FLT3 inhibitor exposure[8,32,59]. Alongside autophagy, metabolic rewiring provides an additional layer of protection. Leukemic cells can flexibly alter glycolysis, oxidative phosphorylation, amino acid utilization, and lipid metabolism according to niche conditions[31,48,60]. Marrow adipocyte-associated signaling and extracellular vesicle-mediated intercellular communication may further support therapeutic adaptation in hematologic malignancies[61,62]. In addition, vascular niche interactions, including endothelial-mediated survival signals, further promote persistence after chemotherapy and targeted therapy[44,63].

Chemokine-mediated retention is another critical mechanism, particularly through the CXCL12/CXCR4 axis[64,65]. This pathway regulates homing and anchorage of leukemic cells within the BMM and is especially important for stem-like compartments[47,64,65]. High CXCR4 activity is associated with enhanced niche dependence and poor clinical outcome in AML[65]. In FLT3-mutated disease, CXCR4 signaling can preserve leukemic survival during FLT3 inhibition and contribute to adaptive resistance by increasing reliance on stromal protection[64-67].

Soluble factors within the marrow also weaken FLT3-targeted therapy. FLT3 ligand can reduce apparent sensitivity to FLT3 inhibitors, while stromal-derived signals can activate bypass pathways that decrease dependence on FLT3[8,18,29,31-33]. Pro-inflammatory cytokines and hematopoietic mediators can further reinforce non-genetic resistance by sustaining MAPK-, STAT-, or other survival pathways despite effective FLT3 blockade[31-33,53,57,58]. These mechanisms are especially important in early adaptive resistance, before stable secondary mutations become dominant[18,30-33]. Finally, immune suppression within the marrow limits clearance of residual disease. Exhausted T cells, immunosuppressive macrophages, and inflammatory niche remodeling create an immune-permissive environment in which resistant leukemic cells can survive and expand[39,40,45,46,58].

THERAPEUTIC STRATEGIES TARGETING FLT3-MUTATED LEUKEMIA AND ITS SUPPORTIVE NICHE

Because therapeutic failure in FLT3-mutated AML reflects both oncogenic kinase signaling and microenvironment-dependent persistence, current treatment strategies increasingly aim to target both compartments[3-6,19]. FLT3 inhibitors remain the therapeutic backbone (Figure 1). Midostaurin and quizartinib have improved outcomes in combination with intensive chemotherapy in newly diagnosed FLT3-mutated AML, while gilteritinib remains a key option for relapsed or refractory disease[3,4]. In transplant-eligible patients, post-transplant FLT3 inhibitor maintenance has become an important strategy to reduce relapse risk, particularly in FLT3-ITD AML, although the optimal drug, timing, and duration are still being defined[23-25,51].

One major direction is rational combination therapy. FLT3 inhibitors combined with venetoclax have shown promising activity in relapsed or refractory FLT3-mutated AML and provide a clinically relevant approach to simultaneously target kinase signaling and apoptosis resistance[27]. Additional combinations with hypomethylating agents or inhibitors of compensatory pathways such as ERK, JAK, or broader polypharmacologic networks are being investigated to suppress adaptive survival signaling[22,27-29]. Novel FLT3-targeted compounds such as FF-10101 and foretinib may also help overcome resistance caused by secondary kinase-domain mutations[25,26]. Additional evidence suggests that marrow-derived adipocyte-associated signals and extracellular vesicle-mediated intercellular communication may also contribute to therapeutic adaptation in hematologic malignancies, supporting these pathways as potential adjunctive targets[61,62]. These approaches are especially attractive because they address both on-target and off-target escape mechanisms[6,11,18,19,25-29].

Disrupting leukemic cell interactions with the marrow niche represents another promising strategy. Inhibition of the CXCL12/CXCR4 axis can mobilize leukemic cells out of protective marrow sites and enhance sensitivity to FLT3 inhibitors[64-66]. Interfering with adhesion-related interactions may likewise weaken stromal protection and reduce LSC persistence[44,53,67]. Given the important role of autophagy in niche-mediated resistance, combining FLT3 inhibitors with autophagy inhibitors may provide an additional means of overcoming microenvironment-enabled survival[8,32,59]. Approaches targeting vascular niche-mediated resistance, including modulation of miR-126-associated endothelial protection, are also emerging as mechanistically relevant strategies[63].

Current and emerging therapeutic strategies targeting FLT3-mutated AML, LSCs, and the supportive bone marrow niche are summarized in Table 2. Metabolic adaptation is another promising therapeutic target. AML stem-like cells frequently depend on oxidative phosphorylation and exhibit altered amino acid and lipid metabolism, which can contribute to persistence during FLT3 inhibitor or venetoclax exposure[48,60,61]. Targeting these metabolic dependencies may sensitize resistant cells to existing therapies[48,60]. More broadly, future effective regimens for FLT3-mutated AML will likely integrate FLT3 inhibition with strategies that dismantle the supportive marrow niche, reverse metabolic adaptation, and restore antileukemic immunity[28,53].

Table 2 Current and emerging therapeutic strategies for FLT3-mutated acute myeloid leukemia and its supportive bone marrow niche.

Strategy	Representative approach	Main rationale	Ref.
FLT3 inhibition	Midostaurin, gilteritinib, quizartinib	Directly suppresses FLT3-driven leukemic signaling	[3,4]
Next-generation FLT3 inhibitors	FF-10101, foretinib	Overcomes resistance associated with secondary FLT3 mutations	[25,26]
FLT3 inhibitor-based combination therapy	FLT3 inhibitor + venetoclax	Simultaneously targets kinase signaling and apoptosis resistance	[27]
Bypass pathway cotargeting	FLT3 inhibitor + ERK/JAK-related inhibition	Suppresses adaptive survival signaling	[22,29]
CXCL12/CXCR4 disruption	CXCR4 inhibitors	Mobilizes leukemic cells from protective marrow niches	[64,65,67]
Autophagy-targeted therapy	FLT3 inhibitor + autophagy inhibition	Counteracts microenvironment-enabled survival programs	[8,59]
Metabolic targeting	OXPHOS/amino acid/Lipid metabolism targeting	Exploits metabolic dependencies of persistent leukemic cells and LSCs	[48,60]
Post-transplant maintenance	FLT3 inhibitor maintenance after allo-HSCT	Reduces relapse risk by suppressing residual disease	[23-25]
Niche-directed strategies	Targeting vascular or stromal protection	Weakens microenvironment-mediated resistance	[53,63]

ERK: Extracellular signal-regulated kinase; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C chemokine receptor type 4; LSCs: Leukemia stem cells; HSCT: Hematopoietic stem cell transplantation.

CONCLUSION

FLT3-mutated AML is sustained not only by constitutive kinase activation, but also by continuous adaptation to the BMM and persistence of LSCs within a remodeled protective niche. Stromal support, adhesion signaling, chemokine-mediated retention, bypass pathway activation, autophagy, metabolic plasticity, hypoxia, and immune suppression collectively contribute to therapeutic resistance and relapse. This explains why FLT3 inhibitor monotherapy rarely produces durable disease eradication. Current evidence supports a treatment model in which FLT3 inhibition is necessary but insufficient. More durable remission will require simultaneous targeting of leukemia-intrinsic oncogenic signaling, microenvironment-dependent survival pathways, and the residual stem-like compartment. Combination strategies involving FLT3 inhibitors, venetoclax, CXCR4 antagonists, autophagy inhibition, metabolic intervention, post-transplant maintenance, and stem-cell-directed immunotherapy appear especially promising. Future progress will depend on improved biological stratification of resistant states, identification of biomarkers of niche dependence, and therapeutic designs aimed not only at reducing blast burden but at eliminating residual LSCs.