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Combined loss of function of two different loci of miR-15/16 drives the pathogenesis of acute myeloid leukemia.

Lovat, Francesca; Nigita, Giovanni; Distefano, Rosario; Nakamura, Tatsuya; Gasparini, Pierluigi; Tomasello, Luisa; Fadda, Paolo; Ibrahimova, Narmin; Catricalà, Silvia; Palamarchuk, Alexey; Caligiuri, Michael A; Gallì, Anna; Malcovati, Luca; Minden, Mark D; Croce, Carlo M.
Proc Natl Acad Sci U S A; 117(22): 12332-12340, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424097
Double knockout of the two miR-15/16 loci in mouse resulted in the development of acute myeloid leukemia (AML). This result suggested that, at least, a fraction of human AMLs could be due to a similar mechanism. We analyzed the role of the two miR-15/16 clusters in 93 myelodysplastic syndrome (MDS) patients divided in three subgroups patients with MDS, patients with MDS before transforming into AML (MDS-T), and patients with AML evolving from MDS (MDS-AML). Then, we tested 139 AML cases and 14 different AML cell lines by assessing microRNA (miRNA) expression, target protein expression, genetic loss, and silencing. MDS-T and MDS-AML patients show a reduction of the expression of miR-15a/-15b/-16 compared to MDS patients. Each miRNA can significantly predict MDS and MDS-T groups. Then, 79% of primary AMLs show a reduced expression of miR-15a and/or miR-15b. The expression of miR-15a/-15b/-16 significantly stratified AML patients in two prognostic classes. Furthermore, 40% of AML cell lines showed a combined loss of the expression of miR-15a/-15b and overexpression of their direct/indirect targets. As potential mechanisms involved in the silencing of the two miR-15/16 loci, we identified a genetic loss of miR-15a and miR-15b and silencing of these two loci by methylation. We identified a potential driver oncogenic role in the loss of expression of both miR-15/16 clusters in the progression of MDS into AML and in AML pathogenesis. The stratification of AML patients, based on miR-15/16 expression, can lead to targeted and combination therapies for the treatment of this incurable disease.