Novel sources of endogenous DNA damage in hematopoietic stem progenitor cells

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Moonjung  Jung
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $235,510
Funding agency: National Heart Lung and Blood Institute

Project Summary
The overarching goal of this training award is to acquire the skills and experience necessary to become an
independent physician scientist with research expertise on fundamental mechanisms of bone marrow failure,
with a final goal of developing novel therapies. Maintaining genome integrity is an essential task for cells that
need to pass correct genetic information to their progeny. Cells are equipped with a variety of mechanisms to
protect their genome including robust DNA repair. Hematopoietic stem cells are especially vulnerable to DNA
damage and rely on Fanconi anemia DNA repair pathway that removes DNA interstrand crosslinks. Patients
lacking the Fanconi anemia proteins invariably develop bone marrow failures. Unfortunately, there is no therapy
that prevents bone marrow failures in Fanconi anemia. While bone marrow failure in Fanconi anemia is thought
to be caused by the inappropriate repair of the DNA interstrand crosslinks, the source of that DNA damage is
poorly understood. Recent studies have implicated endogenous metabolic by-products, such as acetaldehyde
and formaldehyde, in acceleration of disease progression in Fanconi anemia. To identify other sources of DNA
damage, we have performed a CRISPR-Cas9 screen and identified a novel source of endogenous DNA damage
that needs Fanconi anemia pathway for its proper repair. In this application, we propose to validate our impactful
in vitro findings in the mouse hematopoietic stem cells using in vivo transplantation assays and genetically
modified mouse models. We will also assess the type of DNA damage and subsequent cellular consequences,
paying special attention to the genomic instability that is caused by this endogenous source of DNA damage.
We will also test whether any other protective pathways play a role in genome maintenance of hematopoietic
stem cells using an unbiased in vivo CRISPR screen approach. Knowledge gained through our studies may
unveil novel therapeutic targets useful for prevention of bone marrow failures in Fanconi anemia and in the
general population.

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interactions><Patients><Physicians><Physiopathology><Population><Prevention><Primary Erythroid Hypoplasia><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><Reporting><Research><Ribonucleoproteins><Risk><Role><Runt Disease><Scientist><Screening Result><Smoldering Leukemia><Solid Neoplasm><Solid Tumor><Source><Strains Cell Lines><T leukemia cell><T-ALL cell><Testing><Training><Transplantation><Unscheduled DNA Synthesis><Validation><Variant><Variation><Work><acute T-cell lymphoblastic leukemia cell><acute T-cell lymphocytic leukemia cell><acute granulocytic leukemia><acute myeloid leukemia><ages><aldehyde dehydrogenases><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><bone marrow failure syndrome><cell sorting><cell transformation><cell type><clustered regularly interspaced short palindromic repeats screen><congenital aplastic anemia><crosslink><cultured cell line><detoxification><experience><fitness><gene 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