Research we fund

This research proposal will investigate the role of ubiquitin-based protein degradation in acute myeloid leukemia (AML). Specifically, we will assess the function of the E3 ligase DCAF15 in the development and maintenance of AML. Additionally, we will evaluate DCAF15 as a potential therapeutic target for AML treatment. The outcomes of this project aim to provide a better understanding of AML pathogenesis and create opportunities for personalized therapy.

Loss of chromosome Y (LOY) is common in acute myeloid leukemia (AML) yet the mechanistic and therapeutic roles of LOY remain largely unexplored. Using CRISPR-Cas9 genetic perturbation, I will interrogate individual genes and whole chromosome Y loss in models of pre-leukemic progenitor and human AML cells to determine necessary and sufficient contributors of LOY to phenotypes. This will enable discovery of novel treatment opportunities conferred by loss of chromosome Y.

This study aims to explore how mutant SETBP1 affects histone methyltransferase complexes to drive leukemia-associated gene transcription. I will use biochemical, imaging, and epigenetic methods to assess the effects of SETBP1 mutations on complex formation, genomic localization, and function. I will evaluate if inhibitors can disrupt SETBP1-driven oncogenesis in human leukemia cell lines, hematopoietic cells, and patient samples to identify novel therapeutic targets in SETBP1-mutant leukemias.

Children with Down Syndrome (DS) have a 30-fold increased risk of B-cell Acute Lymphoblastic Leukemia (B-ALL). We aim to identify the cells of origin in DS-B-ALL and define its unique features. Using scRNA-seq, we will create an immune cell atlas to study how trisomy 21 (T21) affects lymphopoiesis, and map the cellular and molecular heterogeneity in DS-B-ALL at disease onset and during relapse. These studies will help understand the B lymphoid defects in T21 and how they predispose to DS-B-ALL.

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.