Abstract
Chronic myeloid leukemia (CML) is a myeloid stem cell neoplasm characterized by an expansion of myeloid progenitor cells and the presence of BCR-ABL1 oncoprotein. Since the introduction of specific BCR-ABL1 tyrosine kinase inhibitors (TKI), overall survival has improved significantly. However, under long-term therapy patients may have residual disease that originates from TKI-resistant leukemic stem cells (LSC). In this work, we analyzed the miRNome of LSC-enriched CD34+CD38−CD26+ and normal hematopoietic stem cells (HSC) fractions obtained from the same chronic phase (CP) CML patients, and stem and progenitor cells obtained from healthy donors (HD) by next-generation sequencing. We detected a global decrease of microRNA levels in LSC-enriched CD34+CD38−CD26+ and HSC fractions from CML-CP patients, and decreased levels of microRNAs and snoRNAs from a genomic cluster in chromosome 14, suggesting a mechanism of silencing of multiple non-coding RNAs. Surprisingly, HSC from CML-CP patients, despite the absence of BCR-ABL1 expression, showed an altered miRNome. We confirmed by RT-qPCR that the levels of miR-196a-5p were increased more than nine-fold in CD26+ (BCR-ABL1 +) vs. CD26− (BCR-ABL1 −) CD34+CD38− fractions from CML-CP patients at diagnosis, and in silico analysis revealed a significant association to lipid metabolism and hematopoiesis functions. In the light of recent descriptions of increased oxidative metabolism in CML LSC-enriched fractions, these results serve as a guide for future functional studies that evaluate the role of microRNAs in this process. Metabolic vulnerabilities in LSCs open the road for new therapeutic strategies. This is the first report of the miRNome of CML-CP CD34+CD38− fractions that distinguishes between CD26+ (BCR-ABL1 +) and their CD26− (BCR-ABL1 -) counterparts, providing valuable data for future studies.
Highlights
Chronic myeloid leukemia (CML) originates from a hematopoietic stem cell (HSC) that acquires the reciprocal translocation t(9;22)(q34;q11) and the Philadelphia chromosome (Ph) (Rowley, 1973)
We extracted total RNA containing the small RNA fraction (
This is the first description of the miRNome of CML-CP LSC-enriched CD34+CD38−CD26+ fraction and its CD26− counterpart
Summary
Chronic myeloid leukemia (CML) originates from a hematopoietic stem cell (HSC) that acquires the reciprocal translocation t(9;22)(q34;q11) and the Philadelphia chromosome (Ph) (Rowley, 1973). Treatment of CML patients was revolutionized by the introduction of specific tyrosine kinase inhibitors (TKI), like imatinib, nilotinib or dasatinib. These TKIs effectively induce apoptosis in leukemic cells in patients with CML in chronic phase (CP) (Druker et al, 1996). The response of patients to TKI treatment is heterogeneous, and about 40% of imatinib-treated patients require a switch of TKI due to intolerance or resistance to treatment (Holyoake and Vetrie, 2017). A subset of TKI-treated CML patients can achieve a deep molecular response during therapy (Holyoake and Vetrie, 2017). Only half of them or even less can sustain a treatment-free remission (Mahon et al, 2010; Etienne et al, 2017; Ross et al, 2018; Saussele et al, 2018)
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