Research we fund

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.

TP53-mutant clonal hematopoiesis (CH) is prevalent in populations that received genotoxic cancer therapy and is associated with elevated risk for therapy-related myeloid neoplasms (t-MNs). Here, I developed a human model of TP53-mutant CH that exhibits clonal expansion upon exposure to olaparib or paclitaxel treatment and identified a targetable synthetic lethality target DOCK1 that might prevent this clonal expansion. I aim to develop targeted therapies of high-risk TP53-mutant CH and t-MNs.

Relapse after allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML) remains a leading cause of mortality. Our studies reveal that AML drives Wilms’ Tumor 1-specific CD8⁺ T cells into a senescent, natural killer-like state that impairs function and persistence. We will target this pathway and engineer costimulatory switch receptors to rejuvenate T-cell receptor–engineered T cells, enabling durable leukemia control and preventing post-HCT relapse.

My program includes three investigator-initiated studies focusing on large B-cell lymphoma (LBCL), including those with central nervous system involvement. These studies incorporate novel agents in untreated and relapsed/refractory LBCL, tailoring treatment based on genomic signatures and the clearance of minimal residual disease. My goal is to conduct practice-changing research that will positively impact patient outcomes, incorporating biomarkers into the decision-making process.

Patients with T-cell lymphomas (TCL) face poor outcomes due to ineffective therapies and lack of validated biologic targets. My proposal evaluates 3 clinical trials: JAK1 inhibition in untreated peripheral TCL, JAK2/PD-1 blockade in relapsed/refractory peripheral and cutaneous TCL, and chemotherapy optimization in HTLV-1-associated TCL. My overall goal is to generate evidence that redefines therapeutic standards and informs the design of future biomarker-driven clinical trials in TCL.

My research aims to understand the genetic drivers of leukemia to develop safer, more effective therapies. I lead the clinical studies of menin inhibitors which resulted in the first FDA approval of this class. I have also established a precision medicine program centered on biomarkers, resistance, and rational combination strategies with menin inhibitors, including advancement of next-generation epigenetic therapies that target aberrant transcription in leukemia.

This program leverages the accessibility of cutaneous T-cell lymphoma (CTCL) to define how interactions among tumor cells, host immunity, and microbes shape disease progression and treatment response. Through integrated clinical trials, multi-omic mapping, and biomarker discovery, it aims to advance precision diagnosis and therapy for patients with CTCL.

My research focuses on dissecting the epigenetic and transcriptional mechanisms in acute myeloid leukemia. Using tools from molecular and structural biology, chemical biology, genomics, bioinformatics, and preclinical models, I aim to decode chromatin dynamics and regulatory landscapes that drive disease progression and therapy resistance. The ultimate goal of my work is to facilitate the development of more effective, targeted treatments to improve patient outcomes.