Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1α-induced metabolic reprograming
Open accessAbstract
As chronic myeloid leukemia (CML) progresses from the chronic phase to blast crisis, the levels of BCR-ABL increase. In addition, blast-transformed leukemic cells display enhanced resistance to imatinib in the absence of BCR-ABL-resistance mutations. In this study, we show that when BCR-ABL-transformed cell lines were selected for imatinib resistance in vitro, the cells that grew out displayed a higher BCR-ABL expression comparable to the increase seen in accelerated forms of the disease. This enhanced expression of BCR-ABL was associated with an increased rate of glycolysis but with a decreased rate of proliferation. The higher level of BCR-ABL expression in the selected cells correlated with a nonhypoxic induction of hypoxia-inducible factor-1alpha (HIF-1alpha) that was required for cells to tolerate enhanced BCR-ABL signaling. HIF-1alpha induction resulted in an enhanced rate of glycolysis but with reduced glucose flux through both the tricarboxylic acid cycle and the oxidative arm of the pentose phosphate pathway (PPP). The reduction in oxidative PPP-mediated ribose synthesis was compensated by the HIF-1alpha-dependent activation of the nonoxidative PPP enzyme, transketolase, in imatinib-resistant CML cells. In both primary cultures of cells from patients exhibiting blast transformation and in vivo xenograft tumors, use of oxythiamine, which can inhibit both the pyruvate dehydrogenase complex and transketolase, resulted in enhanced imatinib sensitivity of tumor cells. Together, these results suggest that oxythiamine can enhance imatinib efficacy in patients who present an accelerated form of the disease.
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Tumor cells have a propensity to synthesize pentose phosphates through a G6PD-independent pathway.
“the observed propensity of tumor cells to synthesize pentose phosphates through a G6PD-independent pathway (Boros et al., 2000; Zhao et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Zhao et al., 2010
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- Authors
- Zhao, F., Mancuso, A., Bui, T. V., Tong, X., Gruber, J. J., Swider, C. R., Sanchez, P. V., Lum, J. J., Sayed, N., Melo, J. V., Perl, A. E., Carroll, M., Tuttle, S. W., & Thompson, C. B.
- Affiliations
- Abramson Cancer Center (US)
- University of Pennsylvania (US)
- BC Cancer Agency (CA)
- South Australia Pathology (AU)
- Corresponding author
- Thompson, C B
- Venue
- Oncogene
- Published
- 2010-03-15
- Volume
- 29
- Issue
- 20
- Pages
- 2962-2972
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC2874611
- OpenAlex
- W2067382049
- Cited by
- 179
- References
- 37
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 4 · 2023: 12 · 2022: 11 · 2021: 7 · 2020: 17 · 2019: 14 · 2018: 12 · 2017: 9 · 2016: 11 · 2015: 13 · 2014: 13 · 2013: 17 · 2012: 10
- FWCI
- 8.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (K01CA129151, P01CA104838, R01CA092660, R01CA105463)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- imatinib resistance, chronic myeloid leukemia, HIF-1α, metabolic reprogramming, glycolysis, pentose phosphate pathway, transketolase, oxythiamine, blast crisis, pyruvate dehydrogenase complex, hypoxia
- MeSH terms
- Imatinib Mesylate, Animals, Hypoxia, Benzamides, Blast Crisis, Glucose, Humans, Male, Mice, Nude, Piperazines, Pyrimidines, Ribose, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Up-Regulation, Gene Expression Regulation, Neoplastic, Fusion Proteins, bcr-abl, Apoptosis, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, RNA, Small Interfering, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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