The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse modelReport as inadecuate




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Journal of Hematology and Oncology

, 10:139

First Online: 11 July 2017Received: 08 May 2017Accepted: 30 June 2017

Abstract

BackgroundAdditional sex combs-like 1 ASXL1 is frequently mutated in myeloid malignancies. Recent studies showed that hematopoietic-specific deletion of Asxl1 or overexpression of mutant ASXL1 resulted in myelodysplasia-like disease in mice. However, actual effects of a -physiological- dose of mutant ASXL1 remain unexplored.

MethodsWe established a knock-in mouse model bearing the most frequent Asxl1 mutation and studied its pathophysiological effects on mouse hematopoietic system.

ResultsHeterozygotes Asxl1 marrow cells had higher in vitro proliferation capacities as shown by more colonies in cobblestone-area forming assays and by serial re-plating assays. On the other hand, donor hematopoietic cells from Asxl1 mice declined faster in recipients during transplantation assays, suggesting compromised long-term in vivo repopulation abilities. There were no obvious blood diseases in mutant mice throughout their life-span, indicating Asxl1 mutation alone was not sufficient for leukemogenesis. However, this mutation facilitated engraftment of bone marrow cell overexpressing MN1. Analyses of global gene expression profiles of ASXL1-mutated versus wild-type human leukemia cells as well as heterozygote versus wild-type mouse marrow precursor cells, with or without MN1 overexpression, highlighted the association of in vivo Asxl1 mutation to the expression of hypoxia, multipotent progenitors, hematopoietic stem cells, KRAS, and MEK gene sets. ChIP-Seq analysis revealed global patterns of Asxl1 mutation-modulated H3K27 tri-methylation in hematopoietic precursors.

ConclusionsWe proposed the first Asxl1 mutation knock-in mouse model and showed mutated Asxl1 lowered the threshold of MN1-driven engraftment and exhibited distinct biological functions on physiological and malignant hematopoiesis, although it was insufficient to lead to blood malignancies.

KeywordsAsxl1 MN1 Hematopoietic stem cell Engraftment AbbreviationsAMLAcute myeloid leukemia

Asxl1Asxl1 G643WfsX12 heterozygous mice

BMCBone marrow cells

CAFCCobblestone-area-forming cell assay

CFCColony-forming cell

ChIP-SeqChromatin immunoprecipitation sequencing

CMPCommon myeloid progenitors

CRUCompetitive repopulating unit assay

GMPGranulocyte-monocytic progenitors

GSEAGene Set Enrichment Analysis

H3K27me3Tri-methylation of Histone 3 at lysine 27

HPCHematopoietic progenitors

HSCHematopoietic stem cells

HSPCHematopoietic stem cells and progenitors

LKlinc-KitSca-1 cells

LSKlinc-KitSca-1 cells

LSKlinc-KitSca-1 cells

LTC-ICLong-term culture-initiating cells

MDSMyelodysplastic syndrome

MEPMegakaryocyte-erythroid progenitors

WTWild-type control mice

Electronic supplementary materialThe online version of this article doi:10.1186-s13045-017-0508-x contains supplementary material, which is available to authorized users.

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Author: Yueh-Chwen Hsu - Yu-Chiao Chiu - Chien-Chin Lin - Yuan-Yeh Kuo - Hsin-An Hou - Yi-Shiuan Tzeng - Chein-Jun Kao - Po-Han Ch

Source: https://link.springer.com/







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