Research we fund

Acute myeloid leukemia (AML) is the leading cause of leukemia-related deaths despite intensive chemotherapy and stem cell transplantation. New approaches are urgently needed to improve survival. My research focuses on optimizing chimeric antigen receptor (CAR) T cells that target CLEC2A, a newly identified AML-specific target. I aim to expand the therapeutic potential of CLEC2A CAR T cells to safely and effectively treat AML and explore how prior treatments influence CAR T cell response.

Our proposal aims to expand upon a novel, successful strategy to treat chronic myelomonocytic leukemia. It involves use of a novel oral medication (can be taken as a pill) called onvansertib to selectively kill cancer cells and spare normal ones. The goal is to add an arm to study combination of this effective medication with decitabine which is already an approved medication for this cancer.

This five-year study will implement, evaluate, and scale a multilevel intervention to improve clinical trial enrollment among adolescents and young adults and older adults with blood cancers. The intervention combines real-time electronic health record (EHR)-based identification of potentially eligible patients with coordinated provider support, patient-centered trial matching, and navigation through Blood Cancer United’s Clinical Trial Support Center. It will be tested in a three-arm randomized trial at Columbia University Irving Medical Center and adapted for community oncology affiliates, generating real-world evidence to support broader dissemination.

Acute myeloid leukemia (AML) is subject to macrophage-mediated immune clearance, although the mechanisms remain poorly understood. Using genome-wide CRISPRi screens in AML cells co-cultured with macrophages, we identified new regulators of susceptibility to phagocytosis, including a therapeutically targetable link to RHOA signaling. I will dissect the underlying mechanisms and test combinatorial RHOA and PI3Kγ inhibition to nominate novel treatment strategies that overcome AML immune evasion.

MYST family acetyltransferases KAT6A and KAT7 are targetable dependencies in MLLr and NPM1-mutant AML. However, it is unclear how they regulate gene expression and if they have distinct or partially redundant roles. We will deploy systems where endogenous KAT6A or KAT7 can be rapidly degraded, to understand how these proteins regulate chromatin and transcription. By elucidating how KAT6A/KAT7 sustain oncogenic programs, we hope to define how best to use KAT6 and KAT7 inhibitors for AML therapy.

In this study, I will co-opt macrophage quality assurance mechanisms for hematopoietic stem cells (HSCs) to develop a new macrophage-based therapy for AML. I found SFK inhibition increases ‘eat me’ signal Calreticulin (CALR) on leukemic stem cells (LSCs) surface without harming normal HSCs. In this project, I will employ phosphoproteomics and murine models to identify SFK-dependent regulators of CALR and conduct SFK-/- studies in zebrafish to investigate CALR regulation and AML immune clearance.

Myelodysplastic syndromes (MDS) are blood cancers caused by gene mutations that have few treatment options. We are focused on understanding how mutations cause MDS to develop and make the disease worse. We use whole genome sequencing (WGS) of blood cells at serial timepoints to track mutations in patients who are at high risk for developing MDS or already have MDS. By better understanding the genetic changes that cause MDS, we hope to find ways to help prevent it from developing and progressing.

This project explores methionine metabolism as a therapeutic target in acute myeloid leukemia (AML). Methionine addiction is a hallmark of many malignancies. In AML, enzymes and transporters related to methionine metabolism are specifically upregulated in poor-risk and treatment-refractory disease. By characterizing this metabolic dependency, this work aims to establish a mechanistic foundation for exploiting methionine metabolism as a novel treatment strategy in AML.

AML is an heterogenous disease with dismal overall survival rates. This is partly due to the presence of leukemic stem cells that drive disease recurrence. LSCs rewire their metabolism to adapt to therapy. Using unbiased lipidomic analysis comparing LSCs to HSPCs, we identified LSCs to be reliant on fatty acid elongase, ELOVL1. By integrating lipidomic, transcriptomics and functional assays, we aim to uncover why AML LSCs rely on ELOVL1 and pave the way for novel therapeutic strategies in AML.

Myelofibrosis (MF) is a rare blood cancer with few curative options besides allogeneic stem cell transplant, which has high mortality and relapse rates. We will use spatial transcriptomics to map interactions between mutant MF cells and immune cells in bone marrow samples from patients before and after transplant. Our goal is to identify immune mechanisms that control or fail to eliminate mutant clones, potentially leading to better prediction and prevention of post-transplant relapse.