Bortezomib synergizes with homoharringtonine in FLT3-ITD-relapsed/refractory acute myeloid leukemia by inducing FLT3-ITD protein degradation

  • Clin Exp Med. 2026 May 20;26(1):267. doi: 10.1007/s10238-026-02182-8.
Ming Wei  #  1  2 ,  Furong Wang  #  1  2 ,  Dan Huang  1  2 ,  Zhijie Kang  1  2 ,  Yan Yang  1  2 ,  Chengtao Zhang  3  4 ,  Jiacheng Lou  5 ,  Jinsong Yan  6  7  8
Affiliations
  • 1. Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, 116027, China.
  • 2. Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Dalian Key Laboratory of Hematology, Blood Stem Cell Transplantation Institute, Diamond Bay Institute of Hematology, The Second Hospital of Dalian Medical University, Dalian, 116027, China.
  • 3. Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, 116027, China. [email protected].
  • 4. Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Dalian Key Laboratory of Hematology, Blood Stem Cell Transplantation Institute, Diamond Bay Institute of Hematology, The Second Hospital of Dalian Medical University, Dalian, 116027, China. [email protected].
  • 5. Department of Pediatrics, Pediatric Oncology and Hematology Center, The Second Hospital of Dalian Medical University, Dalian, 116027, China. [email protected].
  • 6. Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, 116027, China. [email protected].
  • 7. Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Dalian Key Laboratory of Hematology, Blood Stem Cell Transplantation Institute, Diamond Bay Institute of Hematology, The Second Hospital of Dalian Medical University, Dalian, 116027, China. [email protected].
  • 8. Department of Pediatrics, Pediatric Oncology and Hematology Center, The Second Hospital of Dalian Medical University, Dalian, 116027, China. [email protected].
  • # Contributed equally.
PMID: 42159798 DOI: 10.1007/s10238-026-02182-8
Abstract

Mutations in Fms-like tyrosine kinase 3 (FLT3) are strongly associated with relapse and resistance in Acute Myeloid Leukemia (AML) patients, and the treatment of relapsed or refractory AML (R/R AML) remains a major clinical challenge. We previously conducted a prospective clinical trial on R/R AML with chemotherapy regimen BHA (bortezomib, homoharringtonine and cytarabine), which demonstrated promising efficacy in patients with FLT3-mutated R/R AML. However, the therapeutic mechanism remains unclear. In this study, we aim to elucidate the therapeutic mechanism of BHA regimen on the basis of its efficacy for FLT3-mutated R/R AML. We retrospectively analyzed twenty-nine patients with R/R AML, after one course of therapy, patients harboring FLT3 mutations had a significantly higher complete remission/complete remission with incomplete hematologic recovery rate than those without FLT3 mutations (46.67% vs. 7.14%, respectively; P = 0.035). To further explore the underlying mechanisms, we conducted combination index analysis, inhibition of proliferation and Apoptosis assays. Compared with 293 T-FLT3 cells, 293 T-FLT3-ITD cells were more sensitive to bortezomib, with significantly lower IC50 values. Bortezomib in combination with homoharringtonine had a synergistic effect on FLT3-ITD cells. Moreover, compared with monotherapy, the combination of bortezomib (4 nM) and homoharringtonine (1 nM) markedly increased total cell death in FLT3-ITD cell lines (MV4-11 and Molm-13). Mechanistically, bortezomib promoted the degradation of FLT3-ITD protein, and the degradation of FLT3-ITD protein was further enhanced by homoharringtonine. Notably, this degradation effect was partially reversed by chloroquine. These findings demonstrate that bortezomib and homoharringtonine have synergistic effects and lead to degradation of FLT3-ITD oncoprotein, potentially contributing to a higher complete remission rate in FLT3-ITD R/R AML.

Keywords
AML; Bortezomib and homoharringtonine; Degradation; FLT3-ITD.
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