Research we fund

DNMT3A is a critical tumor suppressor in hematologic malignancies; DNMT3A protein levels affect both tumor latency and type. DNMT3A is regulated in part by protein stability, but the mechanisms remain incompletely understood. Here, I will dissect the mechanisms that regulate DNMT3A protein turnover using CRISPR screening and genetically engineered mouse leukemia models. This work will reveal whether its stabilization could contribute to a new therapeutic approach for hematologic malignancies.

Project Term: July 1, 2023 - June 30, 2026

This work focuses on characterizing the role of FAM72A in EBV-driven B cell tumorigenesis. This protein is upregulated by EBV during the transformation of B cells and overexpressed in many hematologic cancers. Using a combination of in vitro and in vivo EBV transformation models, high-throughput drug screens, and structural analysis we aim to find small molecules inhibitors that target FAM72A and determine if these drugs can prevent or hinder EBV-associated B cell malignancies.

Project Term: July 1, 2023 - June 30, 2026

This research will investigate blood stem cell mutations associated with progression of myeloproliferative neoplasm (MPN) to secondary acute myeloid leukemia (sAML). Our preliminary data suggest that pre-leukemic cells with particular mutations may have a selective advantage in a background of certain MPN subtypes. We will confirm this by utilizing mouse models and both MPN and sAML primary patient samples. Ultimately, we will examine and test inhibition of mechanisms which drive MPN to sAML.

Project Term: July 1, 2023 - June 30, 2026

Inhibition of the PD-1 exhaustion pathway enables the immune system to attack cancers. PD-1 blockade is now a standard treatment for relapsed classic Hodgkin Lymphoma (cHL) and a component of experimental frontline therapy. In patients with cHL, a newly identified population of monocytes/macrophages limits the efficacy of PD-1 blockade. We will characterize and target these tumor-programmed monocytes/macrophages for therapeutic benefit in patients with cHL and other lymphoid malignancies.

Project Term: July 1, 2023 - June 30, 2026

The microbiome is increasingly recognized as contributing to chronic graft-versus-host disease (cGVHD). I hypothesize that microbial antigens drive the devastating complication of bronchiolitis obliterans syndrome (BOS). To determine if such antigen targets are at the heart of BOS pathology, I will integrate spatial transcriptomic approaches, immunopeptidome analysis, and direct antigen specificity testing of TCRs from biospecimens collected from preclinical models and patient biospecimens.

Project Term: July 1, 2023 - June 30, 2026

This project focuses on how age-associated clonal hematopoiesis (CH) alters the bone marrow (BM) microenvironment, and whether this promotes transformation of CH to acute myeloid leukemia (AML). I will utilize single cell RNA-seq data, genetic knockout models, and targeted inhibitors to perturb the non-hematopoietic and hematopoietic compartments of a mouse model of CH. The goal is to determine if manipulation of the BM microenvironment can attenuate CH and prevent AML transformation.

Project Term: July 1, 2023 - June 30, 2026

MLL1/KMT2A rearranged leukemias are the most common blood cancer occurring in children characterized by dismal prognosis. Given the importance of fusion proteins in driving the disease, I will determine factors affecting the fusion protein stability through a CRISPR/Cas9 screening approach in an innovative model system where the MLL fusions are endogenously tagged with a fluorescent protein. This will facilitate development of molecular glue degraders specifically targeting the MLL fusions.

Project Term: July 1, 2023 - June 30, 2026

Our research aims to discover key driving factors in leukemia that regulate mRNA processing. The proposed experiments utilize a combination of biochemical, cell-based, and high-throughput sequencing approaches using human leukemia cell lines and primary patient samples. These studies will reveal factors that are essential for leukemic maintenance, uncover molecular details of mRNA processing, and inform the development of novel therapeutic strategies.

Project Term: July 1, 2023 - June 30, 2026

The reason why some patients with clonal hematopoiesis progress to overt myeloid malignancies is not understood. I will revert epigenetic changes in isogenic in-vitro and in-vivo models of stepwise progression of cohesin-mutant myeloid neoplasia to mechanistically address how changes in genome organization and enhancer regulation drive clonal selection. These studies will improve our understanding of myeloid disease progression and inform therapeutic options to intercept this step.

Project Term: July 1, 2023 - June 30, 2026

GATA2 deficiency is an inherited pediatric syndrome with a high rate of progression to myeloid malignancy, the mechanisms of which remain largely undefined. Here, we will use our recently generated mouse model, Gata2R396Q, to determine the effects of GATA2 deficiency on hematopoietic function and identify novel drivers of myeloid malignancy via focused CRISPR screens. Our work will provide further insight into the mechanisms driving leukemic progression of this syndrome.

Project Term: July 1, 2023 - June 30, 2026

We aim to understand the mechanism of how dysregulated Gasdermin D(GSDMD) protein propels the pathogenesis of myelodysplastic syndromes(MDS). With single-cell sequencing and patient-derived xenograft (PDX) mouse models, we want to provide pre-clinical grade data to support the concept of inhibiting GSDMD as an effective therapeutic approach in the treatment of MDS. We expect to see the great beneficial effects of GSDMD inhibition in MDS mouse models and PDX mouse models using FDA-approved drugs.

Project Term: July 1, 2023 - June 30, 2025

I aim to develop an accurate disease monitoring system and identify immunologic determinants of development and progression in T-cell lymphoma (TCL). I will integrate noninvasive liquid biopsy methods by high-throughput sequencing. I will study blood samples at various milestones, including pre-diagnostic, diagnostic/baseline, and post-treatment specimens during the natural history of TCL. Using these novel tools and unique specimens, my goal is the development of effective therapies for TCL.

Project Term: July 1, 2023 - June 30, 2025