Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells
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Simona Salati1, Valentina Salvestrini2, Chiara Carretta1, Elena Genovese1, Sebastiano Rontauroli1, Roberta Zini1, Chiara Rossi1, Samantha Ruberti1, Elisa Bianchi1, Greta Barbieri1, Antonio Curti2, Fausto Castagnetti2, Gabriele Gugliotta2, Gianantonio Rosti2, Micaela Bergamaschi3, Agostino Tafuri4, Enrico Tagliafico5, Roberto Lemoli3 and Rossella Manfredini1
1Center for Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
2Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy
3Department of Internal Medicine (DiMI), Clinic of Hematology, University of Genoa, IRCCS Azienda Ospedaliera Universitaria S. Martino-IST, Genoa, Italy
4Department of Clinical and Molecular Medicine, Clinic of Hematology, University “La Sapienza”, Rome, Italy
5Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy
Rossella Manfredini, email: [email protected]
Simona Salati, email: [email protected]
Keywords: chronic myeloid leukemia, leukemic stem cells, tyrosine kinase inhibitors, microRNAs, apoptosis
Received: January 10, 2017 Accepted: April 24, 2017 Published: May 08, 2017
The development of Imatinib mesylate (IM), which targets the oncogenic BCR-ABL 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 TKI-resistance 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.
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