American Association for Cancer Research
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Supplementary files from MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis

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posted on 2023-03-31, 02:02 authored by Maria C. Trissal, Terrence N. Wong, Juo-Chin Yao, Rahul Ramaswamy, Iris Kuo, Jack Baty, Yaping Sun, Gloria Jih, Nishi Parikh, Melissa M. Berrien-Elliott, Todd A. Fehniger, Timothy J. Ley, Ivan Maillard, Pavan R. Reddy, Daniel C. Link

Supplementary Materials and Methods// Supplementary Figure 1. Supporting Figure 1. MIR142 mutations attenuate miR-142-3p and miR-142-5p functions.// Supplementary Figure 2. Supporting Figure 2. Mir142 loss alters differentiation in mature hematopoietic populations.// Supplementary Figure 3. Supporting Figure 3. Mir142 loss alters differentiation in MPPs and HSCs.// Supplementary Figure 4. Supporting Figure 4. Mir142-/- bone marrow exhibits reduced repopulating activity with a loss of HSC lymphoid potential.// Supplementary Figure 5. Supporting Figure 7. Mir142 loss enhances IDH2R172K disease initiating capacity.

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National Cancer Institute

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ARTICLE ABSTRACT

Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased ASH1L protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors. Mir142 loss also enhanced the disease-initiating activity of IDH2-mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing HOXA9/A10 expression during normal myeloid differentiation. AML-associated loss-of-function mutations of MIR142 disrupt this negative signaling pathway, resulting in sustained HOXA9/A10 expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation.Significance: These findings provide mechanistic insights into the role of miRNAs in leukemogenesis and hematopoietic stem cell function. Cancer Res; 78(13); 3510–21. ©2018 AACR.

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