Research we fund

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.

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.