Functional Interaction of BRCA1 and CREBBP in Murine Hematopoiesis

Sam R. Holmstrom, Ranjula Wijayatunge, Kelly McCrum, Victoria E. Mgbemena, Theodora S. Ross

Research output: Contribution to journalArticle

Abstract

Both BRCA1 and CREBBP are tumor suppressor genes that are important for hematopoiesis. We have previously shown that mouse Brca1 is essential for hematopoietic stem cell (HSC) viability. In contrast to Brca1 deficiency, which results in pancytopenia, we report here that Crebbp deficiency results in myeloproliferation associated with an increase of splenic HSCs as well as a lethal systemic inflammatory disorder (LD50 = 86 days). To investigate the interaction of these two proteins in hematopoiesis, we generated double Crebbp/Brca1 knockout mice (DKOs). To our surprise, DKOs had accelerated bone marrow failure compared with Brca1-deficient mice and this was associated with an even shorter lifespan (LD50 = 88.5 versus 33 days). Furthermore, Crebbp or Brca1 heterozygosity influenced the hematopoietic phenotype associated with complete deficiency of Brca1 or Crebbp, respectively. We also observed lower BRCA1 protein levels in hematopoietic tissues when CREBBP is absent. Collectively, these data suggest Crebbp and Brca1 functionally interact to maintain normal hematopoiesis.

Original languageEnglish (US)
Pages (from-to)809-820
Number of pages12
JournaliScience
Volume19
DOIs
StatePublished - Sep 27 2019

Keywords

  • Biological Sciences
  • Cell Biology
  • Molecular Biology
  • Physiology

ASJC Scopus subject areas

  • General

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    Holmstrom, S. R., Wijayatunge, R., McCrum, K., Mgbemena, V. E., & Ross, T. S. (2019). Functional Interaction of BRCA1 and CREBBP in Murine Hematopoiesis. iScience, 19, 809-820. https://doi.org/10.1016/j.isci.2019.08.031