An investigation of metabolic vulnerabilities in chronic myeloid leukaemic stem cells

[摘要] Chronic myeloid leukaemia (CML) is a myeloproliferative disorder that originates at the haematopoietic stem cell (HSC) level. CML is driven by BCR-ABL, a fusion oncoprotein with a constitutive tyrosine kinase activity. The discovery of imatinib, a c-Abl specific tyrosine kinase inhibitor (TKI), revolutionised the treatment of CML by inducing cytogenetic and molecular responses in the majority of CML patients in chronic phase. However, imatinib and second/third generation TKIs do not eradicate leukaemic stem cells (LSCs), leading to disease persistence with associated risk of toxicity, drug resistance and relapse. This suggests that effective eradication of CML LSCs requires identification of novel target(s) that can be exploited therapeutically in combination with TKI treatment.In recent years, a plethora of studies have demonstrated that cancer cells rewire their metabolism to fuel their high energy demands and targeting these metabolic alterations can be of therapeutic benefit. Thus far, investigation of CML LSCs metabolism has been restricted by technical limitations. In this study, we aimed to identify and target the metabolic dependencies in CML LSCs using stem cell-enriched (CD34+) primary cells isolated from CML patients and healthy donors. We initially investigated the metabolism of differentiated CD34- and primitive CD34+ cells and demonstrated that glucose and fatty acid oxidation was elevated in CD34+ CML cells. We as well demonstrated that CML CD34+ cells displayed an increase in their mitochondrial oxygen consumption rate (OCR). Next, we compared the metabolism of CD34+ and CD34+CD38- CML cells to their respective normal counterparts, which revealed that stem cell-enriched CML cells possess increased mitochondrial functions in comparison to normal cells. Of clinical significance, we show that the antibiotic tigecycline, an inhibitor of mitochondrial translation, reduced this aberrant oxidative metabolism. The combination of imatinib and tigecycline targeted primitive CML cells at a clinically achievable concentration while having minimal effect on colony formation potential of CD34+ cells derived from healthy donors. To validate these findings in vivo, human CML CD34+ cells were injected into irradiated immune-deficient mice. Remarkably, four-week combination treatment with tigecycline and imatinib in vivo eliminated the majority of CML LSCs, targeting 95% of the cells. Moreover, mice maintained low levels of CML LSCs upon discontinuation of the combination treatment whereas imatinib-treated mice showed signs of relapse.These results indicate that oxidative phosphorylation is crucial for the survival of CML LSCs and inhibition of mitochondrial metabolism with tigecycline, in combination with imatinib treatment, might be a suitable therapeutic strategy to selectively target these cells and improve cure rates.

[发布机构] University:University of Glasgow;Department:Institute of Cancer Sciences

[关键词] Q Science (General)