Research we fund

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.

Sézary syndrome (SS) is an aggressive mature T-cell lymphoma characterized by recurrent mutations in epigenetic modifiers. Mass spectrometry profiling of SS patient samples revealed widespread alterations in histone post-translational modifications (PTMs), including loss of histone H3 lysine 18 monomethylation (H3K18me1), a poorly characterized PTM. We will define the chromatin landscape of H3K18me1, and investigate the role of SCML2, a candidate reader of this mark in lymphomagenesis.

Clonal hematopoiesis (CH) predisposes to hematologic malignancy, but mechanisms are unclear. We identified germline variants at an HSC-associated THRB locus that protect against CH, implicating thyroid hormone signaling in clonal expansion. Using CRISPR perturbation, xenotransplantation, and multi-omics profiling of human HSCs, I aim to define how THRB is regulated and functions in clonal expansion and leukemic progression, revealing targets for prevention and treatment of myeloid malignancies.

Hypomorphic activity of the E1 ubiquitin enzyme, UBA1, has emerged as a driver of myeloid malignancies. However, how dysregulation of UBA1 perturbs protein homeostasis to promote disease remains unknown. The overall objective of this proposal is to determine how hypomorphic UBA1 activity and compensatory UBA6 expression reshape the ubiquitinome in inflammatory-associated myeloid disease and to identify mechanisms of UBA6 regulation that could define novel therapeutic targets.