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Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function

Lin Bai1, Guiying Shi, Xu Zhang

  • 1Key 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.

Experimental Cell Research
|July 16, 2013
PubMed

Insights

Over-expressing BRCA1 in bone marrow disrupts hematopoietic stem cell (HSC) quiescence and differentiation. This leads to HSC exhaustion and impaired B lymphocyte development, highlighting BRCA1

Area of Science:

  • Hematopoiesis
  • Stem Cell Biology
  • Molecular Biology

Background:

  • Hematopoietic stem cells (HSCs) require a balance between quiescence and proliferation for effective hematopoiesis.
  • Loss of HSC quiescence can lead to stem cell exhaustion, emphasizing the need for strict proliferation control.
  • Cyclin-dependent kinases and BRCA1 are implicated in cell cycle regulation, but BRCA1's role in HSCs remains unclear.

Purpose of the Study:

  • To investigate the function of BRCA1 in HSC quiescence and differentiation.
  • To elucidate the mechanisms by which BRCA1 affects HSC behavior in vivo.

Main Methods:

  • Generation of BRCA1 transgenic mice.
  • Analysis of bone marrow cell populations (LSKs, LT-HSCs, ST-HSCs, MPPs).
  • Competitive transplantation assays to assess hematopoietic reconstitution.
  • Evaluation of p21(waf1)/cip1 and p57(kip2) expression levels.

Main Results:

  • BRCA1 overexpression in bone marrow impaired B lymphocyte development.
  • Increased numbers of LSKs, LT-HSCs, ST-HSCs, and MPPs were observed in BRCA1 transgenic mice.
  • BRCA1 transgenic mice exhibited failure in reconstituting hematopoiesis upon transplantation.
  • BRCA1 regulated p21(waf1)/cip1 and p57(kip2) expression, leading to LSK quiescence loss.

Conclusions:

  • BRCA1 overexpression disrupts HSC quiescence and differentiation by down-regulating p21(waf1)/cip1 and p57(kip2).
  • This disruption results in excessive LSK accumulation and impaired hematopoietic development.
  • BRCA1 plays a critical role in maintaining HSC quiescence and function.

Keywords:
BMBRCA1CLPsCMPsFACSGMPHSCHSCsLT-HSCsMEPMPPsST-HSCsbone marrowbreast cancer type 1 susceptibility proteincell cyclecommon lymphoid progenitorscommon myeloid progenitorsfluorescence activated cell sortergranulocyte-macrophage progenitorshemaopoietic stem cellslong-term HSCsmegakaryocyte-erythroid progenitorsmultipotent progenitorsshort-term HSCs

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