Research we fund

The identification of critical therapeutic targets in myeloproliferative neoplasm (MPN) cells will have a significant impact on the development of much needed treatments for the 300,000 MPN patients in the U.S. Deregulated activity of a protein called JAK2 is an important factor that contributes to MPN formation, but currently approved drugs targeting JAK2 have had limited success, as disease-driving cells persistently survive therapy, and thus these drugs can not readily induce remission in patients. After four decades of the identification of the importance of a protein called RAS in cancer, which is also involved in the cancer causing signaling of JAK2 in MPN, an innovative drug has just been developed (in 2024) to directly block RAS activity. This proposal will investigate the potential this exciting new drug may have in novel therapeutic approaches to improve the lives and the long term health and outcomes of MPN patients.

Our objective is to develop a highly specific T-cell engaging therapy to treat a subtype of leukemia that currently lacks effective treatment. We also aim to minimize toxicity to healthy blood cells, a common challenge with existing leukemia immunotherapies.

This project aims to uncover how obligatory heterozygous mutant splicing factors (SF) impact their wildtype counterparts’ functions, RNA interaction sequences and the epitranscriptome and translatome, to identify convergent pathways and novel therapeutic approaches. I will utilize cell lines, mouse models and primary patient samples. I will leverage a spatial spliceoform RNAseq approach to decipher SF mutations’ impact on cell-cell interactions in the bone marrow microenvironment.

This research investigates how the PRMT5-p53-DUSP6 axis regulates cytokine signaling in hematopoietic stem cells and its implications for AML (acute myeloid leukemia) cancers. We will use conditional single and double knockout in vivo models to study PRMT5, p53, and DUSP6 roles, and inducible PRMT5 knockdown AML cell lines to examine PRMT5’s impact on cytokine signaling and AML progression. Our goal is to explore the therapeutic potential of PRMT5-p53-DUSP6 regulation.

This project aims to understand why splicing factor gene mutations paradoxically impair the growth of hematopoietic progenitors. We will use mouse competitive transplants to determine if resolution of R-loops with RnaseH1 and/or curtailing Trp53 activation with Mdm4 restores the growth of splicing factor mutant progenitors. Understanding how these progenitors adapt to growth suppressing signals may nominate novel therapies targeting RNASEH1 or TP53 in MDS patients with splicing factor mutations.

Acute myeloid leukemia remains a highly lethal disease. Menin inhibitors are an exciting new class of drugs in leukemic but are rarely curative and have significant toxicities. We seek to develop a new treatment approach for patients with leukemia by enhancing the effects of Menin inhibitors while limiting their toxicity.

Acute myeloid leukemia (AML) is a heterogeneous malignant blood cancer. Its treatment outcome is influenced by the leukemia-driving mutations. Oncogenic NRAS mutations associate with both AML progression, and multi-drug resistance and treatment failure in AML.

We identified a novel combo treatment that greatly improved the survival of leukemia mice through enhancing the leukemia killing activities of T cells. We will investigate its underlying mechanisms and validate it in human AML patient cells

The cohesin and BAF complexes are both epigenetic regulators of dynamic chromatin accessibility. Recurrent mutations are observed in proteins of both complexes in adverse risk acute myeloid leukemia (AML). We will use Stag2 (cohesin) and Arid1a (BAF) knockout mice and AML cell lines to deconvolve their unique and cooperative roles in hematopoiesis. This proposal will test the hypothesis that their overlapping functions constitute viable therapeutic targets for these recalcitrant patients.

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.