Titles + affiliations
Assistant Professor of Internal Medicine
University of Michigan Medical School
Research
The Role of SRCAP in Hematopoiesis and Leukemogenesis
Summary
Mutations in SRCAP have recently been identified in hematologic disorders such as AML, suggesting the importance of this gene in leukemogenesis. SRCAP is responsible for the deposition of H2A.Z into chromosomes, which remains a poorly understood mechanism of epigenetic regulation. We used a novel mouse model of Srcap loss to determine that it is essential for normal hematopoiesis including stem cell function. Hematopoietic cells lacking this gene had upregulation of p53, a marker of cellular stress. Based on this data and previously identified roles of SRCAP and H2A.Z in the response to DNA damage, we hypothesize that SRCAP is essential for the maintenance of genomic integrity and that disruption of SRCAP function may promote the development of leukemia. Using a mouse model of Srcap loss, mouse leukemia models, and human cell lines, we will determine whether loss of Srcap cooperates with other mutations identified in AML such as AML1-ETO to promote leukemogenesis and assess the impact of Srcap loss on genomic integrity in both non-malignant hematopoietic and leukemic populations. We will then investigate how SRCAP loss impacts H2A.Z occupancy and whether this correlates with sites of genomic damage, altered genome accessibility, or gene expression changes. These studies will significantly increase our understanding of H2A.Z biology. They will also provide insights on how leukemic clones maintain genomic integrity, which may reveal new therapeutic vulnerabilities in AML.
Impact
Mutations in SRCAP have been identified in hematologic disorders such as AML, suggesting the importance of this gene in the development of leukemias. SRCAP is responsible for the deposition of H2A.Z into chromosomes, which remains a poorly understood mechanism of gene regulation. We used a novel mouse model of SRCAP loss to determine that it is essential for normal hematopoiesis including stem cell function. Hematopoietic cells lacking this gene had upregulation of p53, a marker of cellular stress. Based on this data and previously identified roles of SRCAP and H2A.Z in the response to DNA damage, we hypothesize that SRCAP is essential for the maintenance of genomic integrity and that disruption of SRCAP function may promote the development of leukemia.
Understanding the importance of SRCAP-mediated H2A.Z deposition has proven difficult due to the essential of both of these genes. In this Leukemia Research Foundation project, we have developed and characterized a system to knock down the expression of SRCAP in a time-specific manner. In a hematopoietic cell line (MOLM13), we have discovered that downregulation of SRCAP expression causes MOLM13 cells to have a growth disadvantage with evidence of increased DNA damage and moderate p53 activation, which is consistent with our mouse model. After 4 days of SRCAP knockdown, the cells (while already showing signs of their growth disadvantage), don't display evidence of early apoptosis. Thus, we believe that this tool will be useful to understand how loss of SRCAP impacts H2A.Z deposition and how these impact the development of leukemia.
My future research plans include submitting a National Institutes of Health (NIH) R01 grant focusing on how loss of SRCAP impacts H2A.Z deposition in a locus-specific manner and how perturbation of H2A.Z deposition impacts other cellular mechanisms of regulation, hematopoiesis, and leukemogenesis. The tools developed and characterized in this Leukemia Research Foundation project will be critical for the submission of this grant.
Leukemia Research Foundation grant
$100K awarded in 2022
Disease focus
Acute myeloid leukemia (AML)
Research focus
Causes/risk factors (genetics)