title: ASXL1 plays an important role in erythropoiesis.
abstract: ASXL1 mutations are found in a spectrum of myeloid malignancies with poor prognosis. Recently, we reported that Asxl1(+/-) mice develop myelodysplastic syndrome (MDS) or MDS and myeloproliferative neoplasms (MPN) overlapping diseases (MDS/MPN). Although defective erythroid maturation and anemia are associated with the prognosis of patients with MDS or MDS/MPN, the role of ASXL1 in erythropoiesis remains unclear. Here, we showed that chronic myelomonocytic leukemia (CMML) patients with ASXL1 mutations exhibited more severe anemia with a significantly increased proportion of bone marrow (BM) early stage erythroblasts and reduced enucleated erythrocytes compared to CMML patients with WT ASXL1. Knockdown of ASXL1 in cord blood CD34(+) cells reduced erythropoiesis and impaired erythrocyte enucleation. Consistently, the BM and spleens of VavCre(+);Asxl1(f/f) (Asxl1(∆/∆)) mice had less numbers of erythroid progenitors than Asxl1(f/f) controls. Asxl1(∆/∆) mice also had an increased percentage of erythroblasts and a reduced erythrocyte enucleation in their BM compared to littermate controls. Furthermore, Asxl1(∆/∆) erythroblasts revealed altered expression of genes involved in erythroid development and homeostasis, which was associated with lower levels of H3K27me3 and H3K4me3. Our study unveils a key role for ASXL1 in erythropoiesis and indicates that ASXL1 loss hinders erythroid development/maturation, which could be of prognostic value for MDS/MPN patients.
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|State Key Laboratory of Experimental Hematology, Institute of Hematology &Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences &Peking Union Medical College, Tianjin 300020, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Showa University Fujigaoka Hospital, 1-30 Fujigaoka Aoba-Ku, Yokohamashi Kanagawa, 227-8501, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology &Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences &Peking Union Medical College, Tianjin 300020, China.
authors.forename: Mengyao
authors.initials: M
authors.lastname: Sheng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology &Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences &Peking Union Medical College, Tianjin 300020, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Bai
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Runze
authors.initials: R
authors.lastname: Chen
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology &Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences &Peking Union Medical College, Tianjin 300020, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology &Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences &Peking Union Medical College, Tianjin 300020, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D044127:Epigenesis, Genetic; D015672:Erythroid Precursor Cells / Q000502:physiology*; D004920:Erythropoiesis; D006657:Histones / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: C473949:ASXL1 protein, human; D006657:Histones; D012097:Repressor Proteins