Senior Postdoctoral Researcher
I joined the Patel Lab after completing my doctoral dissertation with Peter Kurre on the in utero programming of haematopoietic stem cells at Oregon Health & Science University. My work in Fanconi anemia (FA), a rare recessive disease associated with hematopoietic failure, was the first to demonstrate a prenatal defect in the hematopoietic stem & progenitor cell compartment in an animal model. This both challenged the conventional paradigm of FA-associated bone marrow failure and highlighted a critical window of opportunity for preventative stem cell therapy. I also worked in collaboration with Dr. Daniel Marks's lab at OHSU, investigating nutritional programming of fetal liver hematopoietic stem & progenitor cells via high-fat diet and maternal obesity.
My work in the Patel group is focused on the contribution of endogenous aldehydes to haematopoietic stem cell attrition and carcinogenesis in Fanconi anaemia.
Protection against aldehyde DNA damage is critical for the haematopoietic system
Fanconi anaemia is an inherited disease in which a pathway coordinating the repair of DNA interstrand crosslinks is inactivated. FA is characterised by developmental anomalies, bone marrow failure (often presenting in childhood), and cancer. Most agents known to cause DNA interstrand crosslinks are chemotherapeutic agents such as cisplatin or compounds found in nature such as psoralen, a photoactivated toxin in certain plants; however, the culprits for DNA damage to cells such as haematopoietic stem cells in FA are unknown and are likely to be produced endogenously. Furthermore, mouse models of FA, of which there are now many, have had a remarkably mild phenotype compared to that seen in humans. Several years ago, our lab discovered that genetic inactivation of key aldehyde detoxifying enzymes in conjunction with knocking out the FA pathway revealed a phenotype in mice similar to that seen in humans with FA, including spontaneous pancytopenia, bone marrow failure, and leukaemia. This compelling result suggests that endogenous and diet-derived aldehydes such as formaldehyde and acetaldehyde, which can attack DNA to form crosslinks, may be a missing piece of the puzzle in determining what drives the phenotypes seen in FA. We call the dual protective effect of metabolic detoxification and DNA repair "two-tier protection."
Although the catabolism of endogenous aldehydes is critical for preserving the proper function, genomic integrity, and longevity of haematopoietic stem and progenitor cells, it is not known whether this protection must be cell-intrinsic or extrinsic, when it is required, and where the aldehydes are being produced or how far they may be able to travel from the site of production. My project's focus is determining whether detoxification is required within haematopoietic cells or whether it can be delegated to other tissues such as liver, and examining when in the development of the blood system it is required.
Endogenous DNA damaging agents in squamous cell carcinoma
Humans with FA have an extraordinary, 500- to 700-fold increased risk of developing head and neck squamous cell carcinoma, compared to the general population. However, what drives the development of these cancers in FA is an open question and given that the FA pathway coordinates the complex process of interstrand crosslink repair, it is plausible that DNA damaging-agents are involved. I am investigating what the consequences are of removing two-tier protection from epithelial tissue, whether endogenous aldehydes drive squamous cell carcinogenesis and if so, which aldehydes are involved.
Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans.
Dingler FA. et al, (2020), Mol Cell, 80, 996 - 1012.e9
Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms.
Hodskinson MR. et al, (2020), Nature, 579, 603 - 608
TRAIP is a master regulator of DNA interstrand crosslink repair.
Wu RA. et al, (2019), Nature, 567, 267 - 272
Endogenous DNA Damage Leads to p53-Independent Deficits in Replicative Fitness in Fetal Murine Fancd2 −/− Hematopoietic Stem and Progenitor Cells
Yoon YM. et al, (2016), Stem Cell Reports, 7, 840 - 853
Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes
Huan J. et al, (2015), Leukemia, 29, 2285 - 2295