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.