biostudies-literatureMarshall ACancer Research UKChildren with Cancer UKBritish Heart FoundationKay Kendall Leukaemia FundMedical Research CouncilCrohn's & Colitis FoundationBlood Cancer UKWellcome TrustCHILDREN with CANCER UKJapan Society for the Promotion of Science19390https://www.ebi.ac.uk/biostudies/studies/S-EPMC7656267biostudies-literatureUnknown10(1)AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2^R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2<sup>R14Scientific reportsMir142 loss unlocks IDH2&lt;sup&gt;R140&lt;/sup&gt;-dependent leukemogenesis through antagonistic regulation of HOX genes.PMC7656267KKL8891600112796PG/12/36/29444639089163011JP16H06276MR/N000838/1C416/A2093817-250107387/Z/15/ZDeltcheva ENimmo RGuo YJames CKasturiarachchi JMay GKhwaja ALord GMBrooks SAnandagoda NDatta PGhazaly EMarshall ABrown JLinch DAraki MJackson IHoward JKAraki KEnver TfalseMir142 loss unlocks IDH2&lt;sup&gt;R140&lt;/sup&gt;-dependent leukemogenesis through antagonistic regulation of HOX genes.AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2^R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2<sup>R142020-01-01T00:00:00Z2020 Nov2026-05-07T16:25:34.034Z2020-11-19T15:24:16ZS-EPMC76562673317321910.1038/s41598-020-76218-8