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.
