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

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. Here we show that when BCR-ABL transformed cell lines were selected for imatinib resistance in vitro, the cells that grew out displayed higher BCR-ABL expression comparable to increase seen in accelerated forms of the disease. This enhanced expression of BCR-ABL was associated with an increased rate of glycolysis but a decreased rate of proliferation. The higher level of BCR-ABL expression in the selected cells correlated with a non-hypoxic induction of HIF-1α that was required for cells to tolerate enhanced BCR-ABL signaling. HIF-1α induction resulted in an enhanced rate of glycolysis but reduced glucose flux through both the TCA 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 non-oxidative 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 that present in the accelerated form of the disease.