Tigecycline May Selectively Target Leukemic Stem Cells in CML

ABL-specific tyrosine kinase inhibitors (TKI), including imatinib mesylate, have improved outcomes in patients with chronic myeloid leukemia (CML). However, these drugs primarily target differentiated cells, and persistent residual leukemic stem cells (LSC) can promote resistance or relapse. In order to identify potentially targetable metabolic vulnerabilities in CML LSCs, Kuntz and colleagues performed metabolic profiling to detect steady-state levels of 70 metabolites in CD34⁺ stem-cell enriched CML cells and CD34⁻ differentiated CML cells from four patients with CML, compared with normal hematopoietic CD34⁺ cells from healthy donors. The CD34⁺ CML population exhibited an increase in oxidative metabolism with an increase in glycerol-3-phosphate, carnitine, and acylcarnitine derivatives, and a decrease in free fatty acids, suggesting an increase in lipolysis and fatty-acid oxidation. Moreover, CD34⁺ cells had increased mitochondrial oxygen consumption, an increase in glucose oxidation, and an increase in anaplerosis (reactions that replenish tricarboxylic acid cycle intermediates). Based on these findings, CML LSCs were treated with tigecycline, an FDA-approved antibiotic that inhibits the synthesis of mitochondrial proteins required for oxidative phosphorylation. Single-agent tigecycline inhibited oxidative metabolism and anaplerosis in CD34⁺ CML cells and suppressed their proliferation. Combined treatment with imatinib and tigecycline eliminated colony formation in CD34⁺ CML cells and stringent stem cell assays, but exhibited relatively little toxicity to nonleukemic cells. In a human CML xenotransplantation model, treatment with imatinib plus tigecycline eliminated CD34⁺CD38⁻ CML LSCs and reduced signs of relapse after drug withdrawal compared with single-agent imatinib. The finding that CML LSCs are sensitive to disruption of oxidative phosphorylation, whereas normal CD34⁺CD38⁻ cells are not, suggests the possibility for combination therapy with tigecycline and imatinib to eliminate LSCs and differentiated CML cells to potentially prevent relapse in patients with CML.

Kuntz EM, Baquero P, Michie AM, Dunn K, Tardito S, Holyoake TL, et al. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat Med 2017 Sep 18 [Epub ahead of print].

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