Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis
ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study,...
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doaj-ff04978537104c5eb6767b82a4d152e32021-10-08T06:21:35ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-10-011110.3389/fonc.2021.754093754093Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced LeukemogenesisMohammad B. Aljazi0Yuen Gao1Yan Wu2George I. Mias3George I. Mias4Jin He5Department of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United StatesDepartment of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United StatesDepartment of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United StatesDepartment of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United StatesInstitute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United StatesDepartment of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United StatesASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-AF9-induced leukemias.https://www.frontiersin.org/articles/10.3389/fonc.2021.754093/fullMLL1ASH1Lhistone modificationH3K36me2leukemogenesisMLL-AF9 fusion |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mohammad B. Aljazi Yuen Gao Yan Wu George I. Mias George I. Mias Jin He |
spellingShingle |
Mohammad B. Aljazi Yuen Gao Yan Wu George I. Mias George I. Mias Jin He Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis Frontiers in Oncology MLL1 ASH1L histone modification H3K36me2 leukemogenesis MLL-AF9 fusion |
author_facet |
Mohammad B. Aljazi Yuen Gao Yan Wu George I. Mias George I. Mias Jin He |
author_sort |
Mohammad B. Aljazi |
title |
Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis |
title_short |
Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis |
title_full |
Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis |
title_fullStr |
Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis |
title_full_unstemmed |
Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis |
title_sort |
histone h3k36me2-specific methyltransferase ash1l promotes mll-af9-induced leukemogenesis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2021-10-01 |
description |
ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-AF9-induced leukemias. |
topic |
MLL1 ASH1L histone modification H3K36me2 leukemogenesis MLL-AF9 fusion |
url |
https://www.frontiersin.org/articles/10.3389/fonc.2021.754093/full |
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