MicroRNA - 497~195 cluster suppresses cell cycle progression by targeting CCND3/CDK4 in acute lymphoblastic leukemia

Recurrent deletions suggest an important role of proliferation in B cell precursor-acute lymphoblastic leukemia (BCP-ALL). We investigated microRNA (miRNA) function in ALL development. In two independent cohorts of BCP-ALL diagnostic and patient-derived xenograft (PDX) samples we found that low miR-497~195 expression was associated with high risk of early relapse and inferior event-free survival. MiR-497~195 overexpression in PDX samples delayed in vivo engraftment and prolonged survival. By ex vivo study and gene expression profiling we showed that the tumor suppressive role was due to inhibition of CDK4/CCND3-mediated cell cycle progression. We observed a higher proportion of early relapses in cases with low miR-497/195 expression co-occurring with CDKN2A/B deletions, suggesting that the lack of both regulatory mechanisms promotes leukemia aggressiveness. Altogether, we found that poor outcome in BCP-ALL is often associated with co-occurrence of low miR-497~195 expression and deletion of CDKN2A/B. MiR-497~195 cluster plays a tumor suppressor role, inhibiting CDK4/CCND3-dependent cell cycle progression, indicating the potential of targeting cell proliferation in ALL treatment.

Publication History

Article published online:
13 May 2020