title: Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function.
abstract: The balance between quiescence and proliferation of HSCs is an important regulator of hematopoiesis. Loss of quiescence frequently results in HSCs exhaustion, which underscores the importance of tight regulation of proliferation in these cells. Studies have indicated that cyclin-dependent kinases are involved in the regulation of quiescence in HSCs. BRCA1 plays an important role in the repair of DNA double-stranded breaks, cell cycle, apoptosis and transcription. BRCA1 is expressed in the bone marrow. However, the function of BRCA1 in HSCs is unknown. In our study, we generated BRCA1 transgenic mice to investigate the effects of BRCA1 on the mechanisms of quiescence and differentiation in HSCs. The results demonstrate that over-expression of BRCA1 in the bone marrow impairs the development of B lymphocytes. Furthermore, BRCA1 induced an increase in the number of LSKs, LT-HSCs, ST-HSCs and MPPs. A competitive transplantation assay found that BRCA1 transgenic mice failed to reconstitute hematopoiesis. Moreover, BRCA1 regulates the expression of p21(waf1)/cip1 and p57(kip2), which results in a loss of quiescence in LSKs. Together, over-expression of BRCA1 in bone marrow disrupted the quiescent of LSKs, induced excessive accumulation of LSKs, and disrupted differentiation of the HSCs, which acts through the down-regulated of p21(waf1)/cip1 and p57(kip2).
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Chao Yang Strict, Pan Jia Yuan Nan Li No.5, Beijing 100021, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Bai
authors.forename: Guiying
authors.initials: G
authors.lastname: Shi
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D019313:BRCA1 Protein; C493957:Cdkn1a protein, mouse; C493965:Cdkn1c protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050761:Cyclin-Dependent Kinase Inhibitor p57
keywords: BM; BRCA1; CLPs; CMPs; FACS; GMP; HSC; HSCs; LT-HSCs; MEP; MPPs; ST-HSCs; bone marrow; breast cancer type 1 susceptibility protein; cell cycle; common lymphoid progenitors; common myeloid progenitors; fluorescence activated cell sorter; granulocyte-macrophage progenitors; hemaopoietic stem cells; long-term HSCs; megakaryocyte-erythroid progenitors; multipotent progenitors; short-term HSCs