Open AccessmiR‐15a‐5p and miR‐21‐5p contribute to chemoresistance in cytogenetically normal acute myeloid leukaemia by targeting PDCD4, ARL2 and BTG2
Author(s) -
Vandewalle Virginie,
Essaghir Ahmed,
Bollaert Emeline,
Lenglez Sandrine,
Graux Carlos,
Schoemans Hélène,
Saussoy Pascale,
Michaux Lucienne,
Valk Peter J. M.,
Demoulin JeanBaptiste,
Havelange Violaine
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.16110
Subject(s) - daunorubicin , microrna , cancer research , cytarabine , npm1 , myeloid leukemia , chemotherapy , gene , biology , myeloid , oncology , medicine , karyotype , genetics , chromosome
Cytarabine and daunorubicin are old drugs commonly used in the treatment of acute myeloid leukaemia (AML). Refractory or relapsed disease because of chemotherapy resistance is a major issue. microRNAs (miRNAs) were incriminated in resistance. This study aimed to identify miRNAs involved in chemoresistance in AML patients and to define their target genes. We focused on cytogenetically normal AML patients with wild‐type NPM1 without FLT3 ‐ITD as the treatment of this subset of patients with intermediate‐risk cytogenetics is not well established. We analysed baseline AML samples by small RNA sequencing and compared the profile of chemoresistant to chemosensitive AML patients. Among the miRNAs significantly overexpressed in chemoresistant patients, we revealed miR‐15a‐5p and miR‐21‐5p as miRNAs with a major role in chemoresistance in AML. We showed that miR‐15a‐5p and miR‐21‐5p overexpression decreased apoptosis induced by cytarabine and/or daunorubicin. PDCD4 , ARL2 and BTG2 genes were found to be targeted by miR‐15a‐5p , as well as PDCD4 and BTG2 by miR‐21‐5p . Inhibition experiments of the three target genes reproduced the functional effect of both miRNAs on chemosensitivity. Our study demonstrates that miR‐15a‐5p and miR‐21‐5p are overexpressed in a subgroup of chemoresistant AML patients. Both miRNAs induce chemoresistance by targeting three pro‐apoptotic genes PDCD4 , ARL2 and BTG2 .