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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Main Authors: Mohammad B. Aljazi, Yuen Gao, Yan Wu, George I. Mias, Jin He
Format: Article
Language:English
Published: Frontiers Media S.A. 2021-10-01
Series:Frontiers in Oncology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fonc.2021.754093/full
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spelling 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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