Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1α-induced metabolic reprograming

F. Zhao, A. Mancuso, T. V. Bui, X. Tong, J. J. Gruber, C. R. Swider, P. V. Sanchez, J. J. Lum, N. Sayed, J. V. Melo, A. E. Perl, M. Carroll, S. W. Tuttle, C. B. Thompson

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

Abstract

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-1α (HIF-1α) that was required for cells to tolerate enhanced BCR-ABL signaling. HIF-1α 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-1α-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.

Original languageEnglish (US)
Pages (from-to)2962-2972
Number of pages11
JournalOncogene
Volume29
Issue number20
DOIs
StatePublished - May 20 2010
Externally publishedYes

Keywords

  • Cell survival
  • Glucose metabolism
  • HIF-1α
  • Imatinib (Gleevec
  • Pentose phosphate pathway
  • Resistance
  • STI571)

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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