2. Academic Validation
  3. BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP

BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP

  • Cell Death Dis. 2023 Apr 24;14(4):287. doi: 10.1038/s41419-023-05811-2.
Lin Feng # 1 2,  Ruxin Ding # 3,  Xuan Qu # 2,  Yuanchun Li # 4,  Tong Shen 5,  Lei Wang 6,  Ruikai Li 7,  Juan Zhang 3 8,  Yi Ru 3,  Xin Bu 3,  Yang Wang 9,  Min Li 10,  Wenqi Song 11,  Liangliang Shen 12,  Pengxia Zhang 13
Affiliations

Affiliations

  • 1 Key Laboratory of Microecology-immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China.
  • 2 Shaanxi University of Chinese Medicine, Xianyang, China.
  • 3 The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
  • 4 Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
  • 5 Department of Digestive Surgery, Xi'an International Medical Center, Xi'an, China.
  • 6 Xi'an Beihuan Hospital, Xi'an, China.
  • 7 Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 8 Department of Biochemistry and Molecular Biology, College of Life Sciences, Northwest University, Xi'an, China.
  • 9 Tongchuan People's Hospital, Tongchuan, China.
  • 10 Xi'an Eastern Hospital, Xi'an, China.
  • 11 Jiamusi Maternal and Child Health Care Hospital, Jiamusi, Heilongjiang, China.
  • 12 The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China. bioliangshen@163.com.
  • 13 Key Laboratory of Microecology-immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China. pengxiaz@jmsu.edu.cn.
  • # Contributed equally.
PMID: 37095099 DOI: 10.1038/s41419-023-05811-2
Abstract

Imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but the primary and acquired imatinib resistance remains the big hurdle. Molecular mechanisms for CML resistance to tyrosine kinase inhibitors, beyond point mutations in Bcr-Abl kinase domain, still need to be addressed. Here, we demonstrated that thioredoxin-interacting protein (TXNIP) is a novel Bcr-Abl target gene. Suppression of TXNIP was responsible for Bcr-Abl triggered glucose metabolic reprogramming and mitochondrial homeostasis. Mechanistically, Miz-1/P300 complex transactivates TXNIP through the recognition of TXNIP core promoter region, responding to the c-Myc suppression by either imatinib or Bcr-Abl knockdown. TXNIP restoration sensitizes CML cells to imatinib treatment and compromises imatinib resistant CML cell survival, predominantly through the blockage of both glycolysis and glucose oxidation which results in the mitochondrial dysfunction and ATP production. In particular, TXNIP suppresses expressions of the key glycolytic Enzyme, Hexokinase 2 (HK2), and Lactate Dehydrogenase A (LDHA), potentially through Fbw7-dependent c-Myc degradation. In accordance, Bcr-Abl suppression of TXNIP provided a novel survival pathway for the transformation of mouse bone marrow cells. Knockout of TXNIP accelerated Bcr-Abl transformation, whereas TXNIP overexpression suppressed this transformation. Combination of drug inducing TXNIP expression with imatinib synergistically kills CML cells from patients and further extends the survival of CML mice. Thus, the activation of TXNIP represents an effective strategy for CML treatment to overcome resistance.

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