Abstract 3042: <i>MIR142</i> loss-of-function mutations promote leukemogenesis through derepression of <i>ASH1L</i> resulting in increased <i>HOX</i> gene expression
Authors: Juo-Chin Yao, Terrence N. Wong, Maria Trissal, Rahul Ramaswamy, Yaping Sun, Pavan R. Reddy, Daniel C. Link
Journal: Cancer Research (2017)

Abstract MIR142 mutations have been identified in acute myeloid leukemia (AML) and non-Hodgkins lymphoma. In AML, all MIR142 mutations localize to the miR-142-3p seed sequence. We show that mutated MIR142 is unable to suppress several well-known targets of miR-142-3p. Interestingly, the mutations of miR-142-3p result in their preferential loading into the RNA-induced silencing complex, leading to the degradation of miR-142-5p. Accordingly, miR-142-5p expression is decreased in MIR142 mutated AML. Hence, MIR142 mutations in AML disrupt both miR-142-3p/5p functions. Thus, we modeled the effect of MIR142 mutations on hematopoiesis using Mir142-/- mice. We show that loss of miR142 results in significant increases in myeloid hematopoietic stem/progenitor cells (HSPCs), including granulocyte-macrophage progenitors, myeloid-biased multipotent progenitors (CD150- CD48+ Flk2- Kit+ Sca+ lineage-) and CD229- myeloid-biased HSCs (CD150+ CD48- Kit+ Sca+ lineage-). In contrast, there are significant decreases of megakaryocyte-erythroid progenitors and erythroid precursors. Although the number of HSCs is normal in Mir142-/- mice, HSC transplantation suggest that they are myeloid-biased. In AML, MIR142 mutations are commonly found in conjunction with mutations of IDH1/2. To assess the importance of this association, we transduced wildtype or Mir142-/- HSPCs with retrovirus expressing IDH2 R172K and then transplanted into lethally irradiated recipients. Expression of IDH2 R172K alone was sufficient to induce a lethal myeloproliferative neoplasm (MPN). In contrast, Mir142-/- alone did not result in MPN. However, loss of Mir142 cooperates with IDH2 R172K to produce a more severe MPN, with increased CD34+ blasts and more severe anemia. Moreover, secondary transplantation shows that Mir142-/- x IDH2 R172K cells but not IDH2 R172K cells efficiently engraft and induce MPN, suggesting that loss of miR142 increases leukemia-initiating activity. We identify the histone methyltransferase ASH1L as a target gene of miR142 that contributes to altered hematopoiesis in Mir142-/- mice. The 3’-untranslated region of ASH1L has four miR-142-3p binding sites, and luciferase reporter assay shows that miR142 suppresses its translation by 80%. Consistent with this observation, Ashl1 protein expression is 3-fold higher in Mir142-/- bone marrow. ASH1L is a key positive regulator of HOX gene expression. Accordingly, we observed markedly (5-10 fold) increased HoxA9/A10 expression in myeloid progenitors in Mir142-/- mice. Likewise, HoxA9/A10 expression is increased in CD34+ blasts from Mir142-/- x IDH2 R172K transplanted mice. Of note, increased HoxA9 expression has been shown to cooperate with mutant IDH1 to induce AML in mice. Together, these findings support a model in which loss-of-function mutations of MIR142 contribute to hematopoietic malignancies by derepressing ASH1L and inducing HOXA9/10 gene expression. Citation Format: Juo-Chin Yao, Terrence N. Wong, Maria Trissal, Rahul Ramaswamy, Yaping Sun, Pavan R. Reddy, Daniel C. Link. MIR142 loss-of-function mutations promote leukemogenesis through derepression of ASH1L resulting in increased HOX gene expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3042. doi:10.1158/1538-7445.AM2017-3042