Research we fund

Multiple myeloma (MM) relies on the bone marrow (BM) niche to progress to refractory disease. We found that beta blockers alter BM niche elements fostering MM growth and also reduce MM cell survival. Our objective is to elucidate the cellular and metabolic basis of how beta adrenergic signals impact the BM niche and MM progression. Knowledge of the prophylactic and therapeutic utility of beta blockers in MM will unravel new means to target neural niche remodeling fueling this fatal malignancy.

Project Term: July 1, 2022 - June 30, 2025

The goal of this project is to explore a novel immunologic therapeutic target for hematologic malignancies, SIGLEC15 (Sig15). The central hypothesis is that Sig15 is aberrantly expressed in malignant B cells, is released to attenuate immune responses and can be targeted therapeutically to promote immune responses to malignant hematopoietic cells. This work will accelerate therapeutic exploitation of the immune system for the treatment of leukemia and lymphoma by targeting Sig15.

Project Term: July 1, 2022 - June 30, 2025

Young Black patients diagnosed with acute myeloid leukemia (AML) have significantly shorter survival compared to White patients. To comprehensively assess genetic, genomic and biologic contributors to the race-associated survival disparity, we propose a complementary approach that addresses major knowledge gaps in our current understanding of AML biology in Black patients, including the overdue characterization of the Black AML genome and subsequent delineation of biologic response to treatment.

Project Term: October 1, 2021 - September 30, 2024

This project investigates immunogenetic determinants of relapse following allogeneic stem cell transplant for myeloid neoplasia. Herein we will determine molecular modes of inactivation of HLA immunodominant peptide-presentation including HLA mutations, deletion and down modulation as a means of immunoescape. We will also study immunogenetic predictors of the strength of graft vs. leukemia according to the HLA divergence in the context of relapse, TCR repertoire diversity and HLA mutations.

Project Term: November 1, 2021 - October 31, 2024

TP53 mutations are present in 10% of MDS cases and are associated with reduced survival and poor prognosis. However, the effect(s) of TP53 mutations on MDS pathogenesis is unknown. We discovered that MDS cells with TP53 mutations display significant alterations in pre-mRNA splicing due to increased EZH2 activity. We will investigate the mechanisms by which TP53 mutations drive MDS pathogenesis and determine the impact of inhibition of EZH2 and the spliceosome on MDS cells with TP53 mutations.

Project Term: July 1, 2019 - June 30, 2022

AML is characterized by founder mutations in epigenetic regulators that perturb alpha-ketoglutarate flux to block differentiation and rewire metabolism exposing new druggable vulnerabilities. By integrating bioenergetics and 5hmC profiling in primary cells, we have discovered unexpected 2-hydroxyglutarate-independent vulnerabilities for TET2, IDH1, IDH2, WT1, and CEBPA mutations. Here, we propose mutation-directed drug development for AML through targeting of the alpha-ketoglutarate pathway.

Project Term: October 1, 2020 - September 30, 2023

In this proposal we seek a mechanistic understanding how mutations in ATP6V1B2 in FL activate autophagic flux and also maintain mTOR in an active state. Given that 25-30% of FL harbor mutations in various v-ATPase subunits and regulators (ATP6V1B2, APT6AP1, VMA21) we will extend our studies to these genes. We will clarify how and under what circumstances activated autophagy can be targeted in FL, why it works, and what the best molecular targets and drugs are.

Project Term: July 1, 2019 - June 30, 2022

Treatment of AML in infants is especially challenging given unique genetic make-up of the disease as well as specific susceptibilities of the host. We will leverage the RNA Seq data from over 2000 patients to discover and validate novel targets (cell surface proteins), and in collaboration with Dr. Correnti (Protein Scientist) and Dr. Fry (CART development expert) generate and test novel antibodies, ADCs, BiTEs and CARTs directed against leukemia-specific targets in infants.

Project Term: July 1, 2019 - December 31, 2022

Two newly identified structural DNA changes, termed chromothripsis and chromoplexy, result in the formation of new chromosomal structures where multiple genes can be deregulated simultaneously. These events involve the relocation of super-enhancers to the sites of oncogenes, which provides a strong drive for cancer progression, an association with high-risk status, adverse prognosis, and punctuated evolution.

Project Term: July 1, 2019 - June 30, 2022

CRLF2-rearranged ALL is the most common subset of Ph-like ALL, has a very poor prognosis and lacks effective therapy. This project will use two novel approaches to improve treatment. The first is developing proteolysis-targeting chimeras to degrade JAK2 and inhibit constitutive JAK-STAT signaling. In the second approach, we will use CRISPR/Cas9 activating and inhibitory genomic screens to identify cellular dependencies, vulnerabilities and synthetic lethal opportunities for therapy.

Project Term: July 1, 2019 - June 30, 2022

We propose to develop an innovative adaptive cellular immunotherapy (ACIT) utilizing Chimeric Antigen Receptor (CAR)-engineered T cells, which respond to both CD19+ cells and cytomegalovirus (CMV) antigen, namely CMV-CD19 bi-specific T cells, followed by CMV vaccine to further expand the T cells in vivo. We aim to address the unmet need to improve high relapse rate in patients with ALL undergoing hematopoietic cell transplantation (HCT) from a matched or mismatched unrelated/related donors.

Project Term: July 1, 2019 - June 30, 2022

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 induces durable remissions in a significant proportion of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (NHL). However, relapse or progression occurs in ~60% of patients with majority of them experiencing CD19 loss in their tumors. Here, we will characterize the mechanism of CD19 loss in NHLs and develop CD79b CAR T-cell therapy as a novel approach to overcome CAR T resistance due to CD19 loss.

Project Term: July 1, 2019 - June 30, 2022