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

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.

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.