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Institut Pasteur of Shanghai reveals that the chromatin remodeling subunit Baf200 promotes normal hematopoiesis and inhibits leukemogenesis

On February 26, Journal of Hematology & Oncology published the collaborative research work entitled "The chromatin remodeling subunit Baf200 promotes normal hematopoiesis and inhibits leukemogenesis" from Yan Zhang’s unit,  Institute Pasteur of Shanghai, Chinese Academy of Sciences and Bin Zhou’s unit, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.

Hematopoiesis is a continuous process with a rare population of hematopoietic stem cells (HSCs) giving rise to all blood cell types. It is finely orchestrated by both cell-intrinsic factors and microenvironmental clues. Adenosine triphosphates (ATP)-dependent chromatin remodeling SWI/SNF-like BAF and PBAF complexes have been implicated in the regulation of stem cell function and cancers. Several subunits of BAF or PBAF, including BRG1, BAF53a, BAF45a, BAF180, and BAF250a, are known to be involved in hematopoiesis. Baf200, a subunit of PBAF complex, plays a pivotal role in heart morphogenesis and coronary artery angiogenesis. However, little is known on the importance of Baf200 in normal and malignant hematopoiesis.

Under the guidance of Prof. Yan Zhang, Bin Zhou, andSidongXiong, Ph.D candidate LuLu Liu and Xiaoling Wan investigated the function of Baf200 in normal and malignant hematopoiesis by utilizing Tie2-Cre-, Vav-iCre-, and Mx1-Cre-mediatedBaf200 gene deletion combined with fetal liver/bone marrow transplantation. Tie2-Cre-mediated loss of Baf200 causes perinatal death due to defective erythropoiesis and impaired hematopoietic stem cells expansion in the fetal liver. Vav-iCre-mediated loss of Baf200 causes only mild anemia and enhanced extramedullary hematopoiesis. Fetal liver hematopoietic stem cells from Tie2-Cre+, Baf200f/f or Vav-iCre+, Baf200f/f embryos and bone marrow hematopoietic stem cells from Vav-iCre+, Baf200f/f mice exhibited impaired long-term reconstitution potential in vivo. A cell-autonomous requirement of Baf200 for hematopoietic stem cells function was confirmed utilizing the interferon-inducible Mx1-Cre mouse strain. Transcriptomes analysis revealed that expression of several erythropoiesis and hematopoiesis associated genes were regulated by Baf200. In addition, loss of Baf200 in a mouse model of MLL-AF9-driven leukemogenesis accelerates the tumor burden and shortens the host survival.This work uncovered critical roles of Baf200 in both normal and malignant hematopoiesis, and provide a potential therapeutic target for suppressing the progression of leukemia without interfering with normal hematopoiesis.

This study was supported by the National Basic Research Program of China and the National Natural Science Foundation of China.




Legend: Loss of Baf200 accelerates leukemogenesis in MLL-AF9 induced AML. (a) Scheme to investigate the role of endogenous Baf200 in MLL-AF9 induced AML. (b) Survival curve of recipient mice engrafted with leukemia cells from primary recipients in the secondary transplantation assay.

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