Abstract
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.
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Data availability
The microarray dataset analyzed in this study is publicly available through the NCBI Gene Expression Omnibus (GEO) under accession number GEO: GSE9476.
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Acknowledgements
This work was supported by NIH grants R01CA173852, R01CA134777, R01HL146137, and R01HL140961, and Riley Children’s Foundation (R.K.), Big Ten Cancer Research Consortium Heme17-092, Galloway Foundation, Department of Veterans Affairs Merit Review (to U.P.D, H.S.B.). We would also like to dedicate this paper to the memory of our beloved colleague and corresponding author, Dr. H. Scott Boswell, Professor of Medicine, who sadly passed away on April 4th, 2025, during the review process for this manuscript. Dr. Boswell supervised the project, led the associated clinical trial (NCT04079738), and conducted the majority of the experimental work presented here. He also secured the funding that supported this study (Big Ten Cancer Research Consortium Heme17-092, Galloway Foundation, and Department of Veterans Affairs Merit Review). Because his passing occurred after the completion of the research but during manuscript revisions, Dr. Boswell contributed fully to the study design, data generation, and interpretation, and he reviewed earlier versions of the manuscript. However, he was not able to review the final revised version submitted after his passing. We include him as an author in recognition of his indispensable intellectual and scientific contributions.
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S.K.P., S.R., and J.L. conceptualized the study and designed, executed the experiments, analyzed the data, and wrote the manuscript. K.S.R.P performed RNA-seq analysis, analyzed and interpreted the data, and critically revised the manuscript. L.D.C. and H.S., K.J.S., J.W., H.K., and H.S. wrote the manuscript. B.R. and L.P. assisted with the experiments. L.D.M. and I.K. provided reagents, read the manuscript, and provided critical inputs. H.S.B., R.K., and U.D. conceptualized, designed the study, funding acquisition, and wrote the manuscript. All authors read and approved the manuscript.
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Pasupuleti, S.K., Rangaraju, S., Layer, J. et al. FLT3-SYK inhibitor and Ixazomib combination impact HOXA and oxidative stress control by β-catenin, SQSTM1 and NRF2 in AML. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01332-1
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DOI: https://doi.org/10.1038/s41698-026-01332-1
