Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes

Abigail R Marshall ,Jane K Howard ,Yao Guo ,Jagath Kasturiarachchi ,Ian Jackson ,Elitza Deltcheva ,Simon Philip Brooks ,Nelomi Anandagoda ,Preeta Datta ,Masatake Araki ,Gillian May ,John Brown ,Essam Ghazaly ,David C Linch ,Graham Lord ,Tariq Enver ,Asim Khwaja ,Kimi Araki ,Chela James ,Rachael Nimmo

doi:10.1038/s41598-020-76218-8

Abstract

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 IDH2R140Q, 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 IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations.

Highlights

Acute myeloid leukemia (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
The activity of the luciferase reporter was reduced by WT MIR142 expression, but the variant forms all failed to cause downregulation (Fig. 1b). These findings were consistent with those reported by others[8,17] and demonstrated that the MIR142 mutations identified in leukemia patients result in loss of function, providing a strong rationale for using Mir[142] knockout (KO) mice to investigate the role of MIR142 mutations in AML etiology
The oncogenic nature of IDH2 mutations, we initially expected that Hoxa genes would be activated by I DH2R140Q; to our surprise, we discovered that Hoxa[5], Hoxa[7] and Hoxa[9] were expressed at a significantly lower level in IDH2R140Q GMPs (Fig. 6i and Supplementary data file 3)

Summary

Introduction

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. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia This model, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations. Mutations in either IDH1 or IDH2 are common in AML, found in about 20% of cytogenetically normal patients, and occur at three particular residues—R132 in IDH1, and R140 or R172 in IDH2 The mutations at these residues disrupt the ability of the IDH enzymes to convert isocitrate to α-ketoglutarate[2], and, importantly, display neomorphic activity, resulting in the aberrant production of high levels of the oncometabolite R-2-hydroxyglutarate (2-HG), which inhibits the function of dioxygenases. MIR142 was found to be recurrently mutated in another cohort of AML and MDS patients, as well as in some lymphomas[7,8]

Methods

Results

Conclusion