FLT3-SYK inhibitor and Ixazomib combination impact HOXA and oxidative stress control by β-catenin, SQSTM1 and NRF2 in AML.

Acute myeloid leukemia (AML) is sustained by oncogenic signaling and stress-adaptive networks that enable proliferative sustenance and therapeutic resistance. Transcriptomic profiling of AML blasts revealed upregulation of FLT3, SYK, HOXA9/10, and CTNNB1 with elevated oxidative phosphorylation (OXPHOS). Proteasome inhibition induced phosphorylation-dependent ubiquitination and nuclear export of β-catenin, triggering stress signaling (p62/SQSTM1/c-JUN/NRF2) and apoptosis in FLT3ITD mutant AML blasts. Dual targeting of FLT3/SYK (TAK-659) and the proteasome (Ixazomib) showed strong synergy across genetically defined AML subsets, irrespective of FLT3 mutant status. In Tet2-/-;Flt3ITD AML-transplanted mice models, combination therapy markedly reduced leukemic burden, restored CD45.1⁺ normal hematopoiesis, corrected disease-associated cytopenias, and normalized hematopoietic stem and progenitor composition. In our phase I/II clinical trial, this combination therapy induced rapid leukemic clearance, early transcriptional silencing of HOXA/FLT3/NRF2 programs, and durable hematologic responses in refractory AML patients. These findings define a therapeutically targetable axis linking FLT3/SYK/β-catenin signaling to stress adaptation, provide a mechanistic basis for combinatorial targeting in high-risk AML. Trial registration: NCT04079738, Date of registration 03 September 2019.