Hematopoiesis is a highly regulated multistep process. BRCA1, a DNA repair protein well studied for its role in hereditary breast cancer susceptibility, directly interacts with several critical proteins involved in normal hematopoietic stem cell (HSC) function, yet its role in hematopoiesis remains unstudied. Recently, I developed a conditional mouse model with bone marrow-specific deletion of Brca1 in hematopoietic cells and discovered that mice with complete loss of Brca1 function have low blood counts at baseline and spontaneously develop hematologic malignancies. These data provide direct evidence of the importance of BRCA1 for normal hematopoiesis and susceptibility to hematologic malignancies, but the mechanisms remain unknown. The overall objective of this application is to determine how partial and complete BRCA1 deficiencies affect bone marrow function. The work outlined in this grant proposal will determine the specific points during the multistep process of hematopoiesis at which Brca1 acts and whether the defects observed in homozygous Brca1 deficiency are due to abnormalities of differentiation or proliferation (Aim 1). BRCA1 is also emerging as a master regulator of genomic stability. Thus, genomic instability may contribute to malignant transformation in Brca1 deficient hematopoietic cells.
Aim 2 will determine whether Brca1 deficient hematopoietic progenitors demonstrate genomic instability either spontaneously or following cytotoxic exposures. Finally, the only commonly observed BRCA1 deficiency state in humans is heterozygous deficiency. Two small studies have found an increase in hematologic toxicities following chemotherapy exposures in individuals with an inherited BRCA1 mutation.
Aim 3 will determine whether BRCA1 haploinsufficiency in humans causes detectable deficits in hematopoiesis through 1) a case control study examining the frequency and severity of myelosuppressive episodes following chemotherapy in women with an inherited BRCA1 mutation versus controls; and 2) through studies of the hematopoietic differentiation and proliferation potential of HSCs derived from induced pluripotent stem cells from individuals with inherited BRCA1 mutations as compared with controls. Successful completion of this proposal will provide important insights into the etiology of BMF and HM and a system in which to test novel therapeutic approaches.

Public Health Relevance

Investigation of the mechanisms involved in normal bone marrow function has informed our understanding of many blood disorders and has set the groundwork for new, more effective therapies. This proposal will define how BRCA1, a critical protein in the repair of DNA damage, contributes to normal bone marrow function. This work will provide a deeper understanding of pathways that are essential to prevent blood cancers and bone marrow failure and a system in which to test new therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL129088-01
Application #
8950505
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Welniak, Lisbeth A
Project Start
2015-08-15
Project End
2019-05-31
Budget Start
2015-08-15
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
DiNardo, Courtney D; Bannon, Sarah A; Routbort, Mark et al. (2016) Evaluation of Patients and Families With Concern for Predispositions to Hematologic Malignancies Within the Hereditary Hematologic Malignancy Clinic (HHMC). Clin Lymphoma Myeloma Leuk 16:417-428.e2
Vasanthakumar, Aparna; Arnovitz, Stephen; Marquez, Rafael et al. (2016) Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice. Blood 127:310-3
Lewinsohn, Maya; Brown, Anna L; Weinel, Luke M et al. (2016) Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 127:1017-23