Research we fund

Menin inhibitors are a new type of targeted cancer drug designed to block an abnormal protein complex called Menin, KMT2A, and LEDGF, which drives certain genetic forms of acute myeloid leukemia (AML). These drugs can switch off leukemia-causing genes, but by themselves they rarely lead to a cure, and some leukemias develop resistance through mutations in the MEN1 gene that prevent the drug from working properly. Our research has now uncovered additional mutations in MEN1, KMT2A, and LEDGF, genes that help form the same complex, that make leukemia cells resistant in new ways. We believe these changes strengthen the complex’s grip on DNA and blunt the effect of Menin inhibitors. In this project, we aim to understand exactly how these mutations cause resistance and to explore new combination treatments that could make Menin inhibitors more effective for patients with AML.

There is a critical need for new strategies to prevent and treat an aggressive form of leukemia linked to TP53 mutations, which are prevalent in patients who have received cancer treatments and are associated with a poor prognosis. Our preliminary studies suggest that targeting DOCK1 may be a promising therapeutic strategy for eliminating TP53-mutant cells in AML and clonal hematopoiesis, a high-risk condition often preceding AML. In this proposal, we will determine the potential of DOCK1 targeting using both genetic and pharmacologic approaches, and investigate the underlying molecular mechanisms of DOCK1 inhibition to gain a deeper understanding of its function.

Mutations in the ASXL1 gene, among the most common in leukemia patients, lead to the production of abnormal proteins that disrupt the normal function of BAP1, an enzyme that regulates how genes are turned on and off in cells. This project will apply structural, biochemical, and genomic approaches to determine how these mutations alter the ASXL1–BAP1 complex and interfere with normal gene regulation. The findings will advance our understanding of how ASXL1 mutations drive leukemia and guide the development of new targeted therapies.

While T cell engager therapy in multiple myeloma can induce dramatic disease reduction, response duration is variable and curative outcomes remain elusive. The project will explore the novel hypothesis that durable response to T cell engager therapy for patients with myeloma is based on an initial inflammatory response that ignites secondary activation of myeloma specific immune cells. Characterizing this transition and the targets that are recognized is critical for unlocking the curative potential of this treatment.

Complex karyotype acute myeloid leukemia (CK-AML) is an aggressive disease that rapidly develops treatment resistance. We have found that CK-AMLs harbor heterogeneous cell types, including one related to red blood cells; these ‘erythroid’-like cells are more treatment resistant than others. We propose work to gain a better molecular understanding of these erythroid cells and identify new strategies to target them. We believe this knowledge will lead to better outcomes for patients with CK-AML.

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.