Imatinib Resistance Associated With BCR-ABL Upregulation Is Dependent on HIF-1alpha-induced Metabolic Reprograming

Oncogene. 2010 May 20;29(20):2962-72. doi: 10.1038/onc.2010.67. Epub 2010 Mar 15.

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-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Benzamides
  • Blast Crisis
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Fusion Proteins, bcr-abl / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Glucose / metabolism*
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Male
  • Mice
  • Mice, Nude
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • RNA, Small Interfering / pharmacology
  • Ribose / metabolism
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • Benzamides
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • RNA, Small Interfering
  • Ribose
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • Glucose