Research we fund

Mutations affecting RNA splicing factors are the most common class of mutations in patients with myelodysplastic syndromes and related myeloid neoplasms. Although these mutations cause a gain of function, there are no treatments which selectively inhibit the enzymatic activity of the mutant spliceosome. To address this issue, here we have developed a new precision therapeutic that selectively target and eliminate cells carrying cancer-causing mutations affecting the RNA splicing factor U2AF1.

Approximately 25% of Acute Myeloid Leukemia (AML) patients are “Primary-Refractory” (P-R) and fail to go into remission with intensive induction chemotherapy. These patients have limited treatment options and overall survival <1 year. We will investigate mechanisms causing chemoresistance through multi-omic studies of a mouse model of P-R AML driven by Mecom overexpression. The goal of this project is to identify potential new therapeutic approaches for P-R AML patients.

A lack of highly selective surface antigens for Acute Myeloid Leukemia (AML) immunotherapy is a major bottleneck in the development of both CAR T cells and T-cell engaging antibodies.  We aim to identify surface-exposed post-translational modifications (PTMs) unique to AML, using high-throughput LC-MS/MS based surfaceomics. By focusing on these distinct PTMs, we hope to develop precision immunotherapies that eliminate AML cells with minimal off-target effects, improving patient outcomes.

Clonal hematopoiesis (CH) often precedes AML development, yet the molecular basis of CH expansion and progression to AML remains a mystery. By deploying single-cell DNA methylation analysis of longitudinal human in-vitro and in-vivo CH models, I aim to identify DNA methylation defects promoting CH fitness advantage, specifically in response to chronic inflammation. This will facilitate the design of therapies to halt premalignant clonal expansions and ultimately prevent leukemic transformation.

Clonal cytopenia of undetermined significance (CCUS) is a poorly understood precursor condition linking clonal hematopoiesis with myeloid malignancy. Motivated by human biobank data, I developed a novel murine model of neutropenic CCUS and found interleukin-17A to be necessary and sufficient to propel Tet2-deficient clonal outgrowth. The objectives of this project are to define the drivers of interleukin-17A liberation in neutropenic CCUS and the mechanism by which it hastens clonal progression.

Myelodysplastic syndrome (MDS) is a fatal disease with limited therapeutic opportunities. To increase survival rate, it is essential to identify therapeutic targets specific for MDS stem and progenitor cells (MDS-SC), the source of the disease. MDS-SC uniquely upregulate nicotinamide metabolism. We thus aim to understand its importance on MDS-SC function and survival using multi-omics analysis. Completion of the study will have identified a new treatment modality to improve MDS patient outcome.

Outcomes for children with T-ALL and T-LL have improved, yet prognosis for children with relapsed disease is dismal. A critical gap remains in identifying high-risk patients in order to allocate novel targeted therapies or immunotherapies. Building on prior work, I will utilize comprehensive genomic profiling to examine the impact of genetic ancestry on tumor biology and survival outcomes. My goal is to improve risk stratification, guide targeted therapy, and reduce inequity in T-ALL/T-LL.

In-frame mutations affecting the basic leucine zipper (bZIP) domain of C/EBPα characterize a distinct subset of acute myeloid leukemia with relatively favorable prognosis, though five-year overall survival remains roughly 60%. Using new mouse models, this project will identify targets of endogenous bZIP–mutated C/EBPα. We will test whether modulating mutant-specific targets alters disease course in mouse models and in patient-derived xenografts, thereby nominating new approaches to therapy.

EZB lymphomas, driven by BCL2 translocations and EZH2 mutations, induce macrophages to adopt a supportive role, essential for maintaining the malignant phenotype. This reprogramming suppresses phagocytosis and promotes pro-tumor activation, mediated by immune synapse signaling and cytokine release. Our study aims to identify molecular pathways involved in this macrophage reprogramming and explore restoring anti-tumor functions as a therapeutic approach.

Improving survival for patients with diffuse large B-cell lymphoma requires tailoring treatment to lymphoma genetic heterogeneity, addressing minimal residual disease (MRD), and bringing safer, effective therapies for frail patients who cannot tolerate aggressive regimens. I address these challenges with genomic subtype targeted treatment, bispecific antibody to eliminate MRD, and novel treatment for frail patients. My goal is to improve outcomes by bringing biomarkers to standard of care.