PROJECT SUMMARY/ABSTRACT
Acute myeloid leukemia (AML) is an aggressive malignancy with a poor prognosis, owing in part to substantial
intratumor genetic heterogeneity that allows specific subclones to evade even intensive chemotherapy. Genomic
studies have identified the spectrum of frequent mutations in AML and suggest a model of sequential mutational
acquisition. Early mutations are believed to confer a fitness advantage to a stem or progenitor cell enabling clonal
expansion and later mutations within this expanding subclone may confer a proliferative advantage resulting in
overt malignancy. AML can occur de novo, but may also develop in patients with myelodysplastic syndrome
(MDS) or clonal hematopoiesis (CH). Across these disease states, DNMT3A mutations are critical initiating
mutations, suggesting an opportunity to target the founding clone of these malignancies. However, targeting of
DNMT3A mutations remains elusive due to a poor understanding of the mechanisms and specific role(s) of these
mutations in disease.
The objective of this proposal is to elucidate the specific oncogenic mechanisms of two frequent DNMT3A
mutations and to define their functional contributions in the maintenance of CH, MDS, and AML. We hypothesize
that genetic restoration of wildtype DNMT3A will block progression of DNMT3A-mutant CH/MDS/AML and thus
that targeting the initiating DNMT3A mutations can provide a therapeutic option in myeloid disease. Moreover, a
complete understanding of DNMT3A mutations will allow for the identification of targetable vulnerabilities
conferred by these mutations. Specific Aim 1 will utilize inducible mouse models and ex vivo CRISPR screens
to define the phenotypes, mechanisms, and conferred vulnerabilities of two DNMT3A mutations in distinct
functional domains of the protein. Specific Aim 2 will use dual recombinase murine models capable of turning on
and off DNMT3A mutations to determine the reversibility of DNMT3A-mutant CH and to evaluate the oncogenic
dependency of DNMT3A mutations in MDS/AML. The implications of these studies will lead to novel therapeutic
approaches for DNMT3A-mutant malignancies.
This proposal will be conducted in the laboratory of Dr. Ross Levine (the Sponsor), who is the head of the
Molecular Cancer Medicine program. The Levine lab is part of the Human Oncology and Pathogenesis Program
at Memorial Sloan Kettering Cancer Center (MSK), a state of the art cancer research institute. Mentorship will
also be provided by Dr. Kristian Helin (the Co-Sponsor), who is the head of the Center for Epigenetics at MSK.
These affiliations, along with the strong scientific and non-scientific 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.