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<p>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 <i>FLT3</i>, <i>SYK</i>, <i>HOXA9/10</i>, and <i>CTNNB1</i> 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 <i>FLT3</i><sup><i>ITD</i></sup> mutant AML blasts. Dual targeting of FLT3/SYK (TAK-659) and the proteasome (Ixazomib) showed strong synergy across genetically defined AML subsets, irrespective of <i>FLT3</i> mutant status. In <i>Tet2</i><sup><i>-/-</i></sup>;<i>Flt3</i><sup><i>ITD</i></sup> 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月26日

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  • Santhosh Kumar Pasupuleti,
  • Sravanti Rangaraju,
  • Justin Layer,
  • Kanaka Sai Ram Padam,
  • Larry D. Cripe,
  • Hamid Sayar,
  • Katie J. Sargent,
  • Jill Weisenbach,
  • Heiko Konig,
  • Huda Salman,
  • Baskar Ramdas,
  • Lakshmi Reddy Palam,
  • Lindsey D. Mayo,
  • Irum Khan,
  • Utpal P. Davé,
  • H. Scott Boswell,
  • Reuben Kapur

摘要

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.