Research we fund

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.

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.

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.

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.

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.

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.

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.

The development of acute myeloid leukemia (AML) is preceded by a “preleukemic” phase in which mutated hematopoietic stem cells expand due to a fitness advantage. Our work uses prospective models and analysis of patient samples to study how the duration of preleukemia and how the preleukemic clonal burden affect progression to AML. Results of our studies will shed new light on AML pathogenesis and help guide clinical management of preleukemic conditions such as clonal hematopoiesis.

Most patients respond well to drugs that inhibit an important MCL target named BTK. However, almost all of them will eventually relapse and then do very poorly. Inhibition of MALT1, a target which is biochemically downstream of BTK, may rescue many of these patients, and inhibiting both BTK and MALT1 may be better still. Developing a drug that inhibits both targets at the same time, from the beginning of treatment, will avoid some complications and likely be best of all; we will find out.

Our research program’s goal is to identify therapeutically actionable pathways in pre-leukemic and leukemic stem cells in myeloid malignancies. We specifically dissect molecular circuits governing stem cell self-renewal and differentiation, how these change during aging, and contribute to leukemic stem cell evolution and maintenance. Accomplishing this work will enable the rational design of curative intervention and perhaps even prevention strategies for patients with myeloid malignancies.

The goal of this project is to investigate the role of the epigenetic regulator Eleven-Nineteen-Leukemia (ENL) and its cancer mutations in acute myeloid leukemia (AML). Our studies leverage the expertise in chromatin biology, functional genomics, and AML modeling, as well as unique chemical compounds and mouse models. Results from this project will provide novel biological insights into our understanding of AML pathogenesis and facilitate the development of novel epigenetic therapies.

My lab is focused on understanding the pathogenic interplay between oncogenic mutations, chronic inflammation and aberrant metabolism as a driver of the evolutionary processes that culminate in lethal myeloid malignancies. We leverage mouse models and human patient samples to establish modalities for targeting this interplay throughout disease pathogenesis. My long-term goal is to improve patient outcomes by establishing therapies that prevent and/or delay evolution to acute leukemia.