Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells

Simona Salati, Valentina Salvestrini, Chiara Carretta, Elena Genovese, Sebastiano Rontauroli, Roberta Zini, Chiara Rossi, Samantha Ruberti, Elisa Bianchi, Greta Barbieri, Antonio Curti, Fausto Castagnetti, Gabriele Gugliotta, Gianantonio Rosti, Micaela Bergamaschi, Agostino Tafuri, Enrico Tagliafico, Roberto Lemoli, Rossella Manfredini

Research output: Contribution to journalArticle

Abstract

The development of Imatinib mesylate (IM), which targets the oncogenic BCRABL fusion protein, has greatly improved the outcome of Chronic Myeloid Leukemia (CML) patients. However, BCR-ABL-positive progenitors can be detected in CML patients in complete cytogenetic response. Several evidence suggests that CML stem cells are intrinsically resistant to Tyrosine Kinase Inhibitors (TKI), and therefore they represent the most likely candidate responsible for disease relapse. In this work, we investigated the microRNA (miRNA) expression profile of different subpopulations of CML Leukemic Stem Cells (LSCs): Lin-CD34+CD38-and Lin-CD34-CD38-cells. These cell fractions have been previously shown to be endowed with TKI intrinsic resistance. Our analysis identified 33 common deregulated miRNAs in CML LSCs. Among those, 8 miRNAs were deregulated in CML independently from BCR-ABL kinase activity and therefore are likely to be involved in the BCR-ABL-independent resistance to TKI that characterizes CML LSCs. In particular, the up-regulation of miR-29a-3p and miR-660-5p observed in CML LSCs, led to the down-regulation of their respective targets TET2 and EPAS1 and conferred TKI-resistance to CML LSCs in vitro. On the other hand, miR-494-3p down-regulation in CML LSCs, leading to c-MYC up-regulation, was able to decrease TKI-induced apoptosis. These results demonstrate that aberrant miRNA expression in CML LSCs could contribute to the intrinsic TKIresistance observed in these cell populations, and support the development of novel therapies aimed at targeting aberrantly regulated miRNAs or their targets in order to effectively eradicate CML LSCs.

Original languageEnglish
Pages (from-to)49451-49469
Number of pages19
JournalOncotarget
Volume8
Issue number30
DOIs
Publication statusPublished - 2017

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Keywords

  • Apoptosis
  • Chronic myeloid leukemia
  • Leukemic stem cells
  • MicroRNAs
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Oncology

Cite this

Salati, S., Salvestrini, V., Carretta, C., Genovese, E., Rontauroli, S., Zini, R., Rossi, C., Ruberti, S., Bianchi, E., Barbieri, G., Curti, A., Castagnetti, F., Gugliotta, G., Rosti, G., Bergamaschi, M., Tafuri, A., Tagliafico, E., Lemoli, R., & Manfredini, R. (2017). Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells. Oncotarget, 8(30), 49451-49469. https://doi.org/10.18632/oncotarget.17706