Research we fund

Lineage-ambiguous leukemias are high-risk blood cancers with unclear biologic basis and suboptimal treatment options. Here, I will identify the cell of origin of lineage ambiguous leukemia and investigate new therapeutic strategies through in vitro and in vivo experimental modeling approaches and preclinical drug studies in patient-derived xenografts. These studies will clarify the cellular and molecular alterations driving lineage ambiguity and advance a new, rational therapeutic approach.

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

NPM1c and TP53 mutations are exclusive in acute myeloid leukemia (AML) despite both being commonly present in patients, suggesting a fitness disadvantage for cells with co-occurring mutations. However, the mechanisms underlying this exclusivity have not been explored. This project will utilize novel models to dissect the importance of TP53 signaling in NPM1c+ (pre)-leukemic stem cells. Generated results may highlight therapeutic opportunities for improved risk management of NPM1c+ AML patients.

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

The goal of this proposal is to investigate the consequence of the chromatin reader eleven-nineteen-leukemia (ENL) gain-of-function mutations in the pathogenesis of leukemia. Our studies leverage the expertise in the molecular and chromatin biology of chromatin reader in leukemia utilizing mouse model, high resolution image, epigenomic and transcriptomic approaches. Our goal is to understand how chromatin reader contributes to cancer development, progression, and therapeutic outcome.

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

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.

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

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.

Project Term: July 1, 2023 - June 30, 2028

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.

Project Term: July 1, 2023 - June 30, 2028

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.

Project Term: July 1, 2023 - June 30, 2028

Our research seeks to understand how ordered acquisition of oncogenic mutations transforms human hematopoietic stem cells into myeloid malignancies. We leverage patient-derived induced pluripotent stem cells and primary normal and malignant stem cells to study how mutation cooperation drives leukemic progression in vitro and in vivo. Our long-term goal is to identify disease mechanisms and develop targeted therapies to eradicate malignant stem cells.

Project Term: July 1, 2023 - June 30, 2028

The focus of my research is to understand the causes and early-life origins of acute lymphoblastic leukemia (ALL). We use a two-pronged approach: 1) conducting epidemiological studies of ALL in susceptible populations to understand genetic predisposition, and 2) investigating the in utero origins of ALL across subtypes. Our goals are to identify children at the highest risk of developing ALL through genetic screening and to lay the groundwork for precision prevention strategies.

Project Term: July 1, 2023 - June 30, 2028

Pediatric acute lymphoblastic leukemia (ALL) that is resistant to standard therapy is a challenge that has been partially overcome by T-cell therapy, yet relapse still occurs in up to 50%. We are conducting two clinical trials that test a next-generation T-cell therapy and the first incorporation of T-cell therapy into initial therapy. These trials will inform future development and the optimal place for this therapy with the goal of improving cure rates for children with very high risk ALL.

Project Term: July 1, 2023 - June 30, 2028

I aim to identify drivers of pediatric and adolescent/young adult lymphoma disparities so that targeted health equity interventions can be developed. Integration of large datasets, systematic collection of social determinants data in clinical trials, and collaboration with patient advocates will: a) create new population-based resources to study lymphoma outcomes; b) establish a novel framework for equity research in lymphoma clinical trials; and c) identify real-world targets for intervention.

Project Term: July 1, 2023 - June 30, 2028

The genomic architecture of residual CLL and molecular determinants of disease progression after targeted combination therapy are unknown. In a phase 2 study of zanubrutinib and venetoclax in CLL, I will investigate the depth of response and genomic changes using cellular and circulating tumor DNA. Data generated from this proposal will provide foundational evidence to develop genomic markers for non-invasive monitoring of treatment response and precise prediction of outcome.

Project Term: July 1, 2023 - June 30, 2028