Research we fund

This grant proposal aims to uncover inherited resilience to clonal hematopoiesis (CH) and myeloid malignancies (MyMs). Our pilot work has identified a regulatory variant that significantly protects from CH/MyM through downregulation of MSI2 levels in human hematopoietic stem cells (HSCs). We seek to perform rigorous mechanistic studies to identify an RNA network that regulates human HSCs and is modulated through genetic variation to protect them from CH/MyMs.

Mutations in the RNA splicing factor gene SRSF2 occur in 25% of patients with MDS, 50% of patients with chronic myelomonocytic leukemia (CMML), and 25% of AML patients over the age of 65.

We recently developed a cell therapy directed against abnormal proteins on the surface of cells expressing mutant SRSF2. This proposal aims to improve this new form of immunotherapy and extend its benefit to the largest number of patients with myeloid blood cancers.

Certain genetic alterations in Diffuse Large B Cell Lymphomas (DLBCL) render these tumors highly aggressive. Aggressive DLBCLs may also form secondary lymphomas in the brain. The research proposed here will examine the role of a specific class of lipids in the growth of these lymphomas and assess the utility of strategies to lower these lipids or inhibit their production in halting tumor growth.

Blood cancers called myeloproliferative neoplasms occur when one of the blood stem cells picks up a mutation. Some patients stay in the chronic phase of the disease for years whereas others rapidly progress with poor outcome. We recently measured when the cancer mutation first occurs and the rate of expansion of the cancer cells in individual patients. We will develop a method that uses the history of disease in each patient to identify those that are at risk of progression.

We recently identified a pervasive, pathogenically relevant mutational mechanism that targets super-enhancers (SE) in DLBCL, leading to target gene deregulation. Here we will dissect the mechanistic role of 3 highly recurrent hotspots in the BCL6, BTG2 and CXCR4 SEs in driving lymphomagenesis and tumor dependency in vitro and in vivo using novel mouse models. These studies will significantly transform our understanding of DLBCL and identify novel therapeutic targets.

Survival rates for those afflicted with MDS have not improved despite extensive effort to identify the key genetic events in its pathogenesis. This project elucidates the contributions of aberrant NPM1 to hematological disorders, with a focus on mitochondrial fitness and inflammasome activation. The resulting insights into the metabolic, genetic and proteomic requirements of homeostasis that are critical to preventing aging will have a major impact on the treatment of hematological malignancies.

Myelodysplastic neoplasms are malignant disorders driven by expansion of diseased hematopoietic stem cells and progression to leukemia. Our investigations have identified the important role of the transporter of amino acid glutamine SLC38A1 in sustaining metabolic demands of rapidly growing malignant stem cells. The goal of this project is to genetically target this transporter to understand its role on tumorigenesis and progression; and to develop SLC38A1 inhibitors as novel therapeutic tools.

Despite remarkable progress in the last 20 years, multiple myeloma remains an incurable disease. In recent years, 2 CAR T cell products that target BCMA on the myeloma cell have been approved. These products result in remarkable initial responses however the duration of these responses has been disappointing. In this proposal, we will take a novel approach to isolate and characterize myeloma cells that interact with CAR T cells but are not killed by them as a potential resistance mechanism.

The goal of our laboratory is to discover, study, and the translate new leukemia therapies to the clinic. In this project, we are studying a signaling pathway, called PI3 kinase gamma, that we believe is important in patients with AML and might lead to new treatments using drugs that target its activity.

CAR-T cells are made from a patient’s own immune cells, altered so that they specifically recognize and kill the patient’s cancer cells. They are effective in many but not all cases of B-acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL), among other blood cancers. In this proposal we seek to better understand ways to select T cells that will make better CAR-T cells as well as to treat CAR T cells them in ways to make them work better in the cancer patient.