PROJECT SUMMARY/ABSTRACT
Clonal hematopoiesis (CH) is characterized by the outgrowth of a genetically distinct subpopulation of cells in the blood
and is a potential precursor state to acute myeloid leukemia (AML). CH is age-associated, occurring in over 20% of
individuals over age 60, and confers an increased risk of both hematological malignancy and cardiovascular disease. The
most common mutations in CH occur in the epigenetic modifiers DNMT3A, TET2, ASXL1, and IDH2 and these same
mutations are found at high variant allele frequencies in AML consistent with their role as initiating mutations. CH mutations
are known to induce functional changes in hematopoietic stem and progenitor cells (HSPCs); however, the specific
mechanisms underlying these alterations are not understood and genotype-specific therapies for these mutations are lacking.
Given the broad prevalence, comorbidities, and risk of malignant transformation associated with CH, there is an unmet need
to develop novel therapies that can prevent clonal expansion and malignant transformation. The long-term objective of my
doctoral research is to identify genotype-specific therapeutic targets in CH. To date, the lack of a suitable ex vivo platform
for culturing primary murine HSPCs has proved a significant technical challenge preventing the use of unbiased screens to
identify therapeutic targets. As described in Aim 1, my thesis work has established an ex vivo co-culture system that
maintains primary murine HSPCs and that yields phenotypes of CH mutations consistent with prior murine and human
studies. We have used this system to perform CRISPR/Cas9 screens on Dnmt3a-, Tet2-, Asxl1-, and Idh2-mutant HSPCs
and have identified genotype-specific dependencies. Of particular interest, the histone lysine demethylases Jmjd1c and
Kdm3b are strong dependencies observed in Tet2- and Idh2-mutant HSPCs. In Specific Aim 1.1, we will interrogate the
mechanisms by which loss of Jmjd1c or Kdm3b cooperates with mutations in Tet2 or Idh2 to create an epigenetic and
transcriptional state that drives synthetic lethality. In Specific Aim 1.2, we will use preclinical murine models and primary
patient samples to delineate the therapeutic potential of targeting JMJD1C and KDM3B in Tet2 and Idh2-mutant CH and
AML. My postdoctoral research will continue to study CH and AML with a slight switch in focus to elucidating the
underlying epigenetic and transcriptional circuitry responsible for the expansion and transformation of CH-mutant clones.
As detailed in Aim 2, we will apply murine models of CH and AML to barcode individual HSPC clones followed by single-
cell transcriptomic and epigenetic studies to define the factors that allow for clonal expansion and transformation. Overall,
these two projects will offer insights into both the basic mechanisms by which clonal expansion and transformation occur
and potential therapeutic strategies seeking to mitigate this clonal expansion/transformation. This proposal will be conducted
in the laboratory of Dr. Ross Levine at Memorial Sloan Kettering Cancer Center (MSK), a state-of-the-art cancer research
institute. These affiliations, along with the strong assets of the Gerstner Sloan Kettering Graduate School, will provide a
rich set of collaborative, technical, and scientific resources to execute the proposed research and career development plans.