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

Menée à l'aide de lignées cellulaires et d'échantillons sanguins ou d'échantillons de moelle osseuse issus de patients présentant un syndrome myélodysplasique ou une leucémie myéloïde aiguë, cette étude démontre que la perte de l'expression des microARNs miR-15 et miR-16, liée à la méthylation combinée de deux loci, favorise la progression d'un syndrome myélodysplasique vers une leucémie myéloïde aiguë

Résumé en anglais

The loss of miR-15a/16-1 on chromosome 13q14 and miR-15b/16-2 on chromosome 3q25 is critical for the development of AML in mice. We hypothesized that, at least, a fraction of human AML patients could undergo a comparable mechanism. Here, we evaluated the expression of the two miR-15/16 clusters in 93 MDS patients and 139 AML patients. A significant reduction of miR-15a, miR-15b, and miR-16 expression can predict the progression from MDS to AML transformation. We demonstrated in 40% of AML cell lines analyzed, a combined reduction of miR-15a/-15b expression and an overexpression of their direct/indirect targets. MiR-15/16 cluster expression can be a valuable marker to stratify AML patients for a combined therapy, based on venetoclax and anti-ROR1 antibody.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.