Research we fund

p>SIRT5 is a master regulator of central energy metabolism. The survival and growth of Acute Myeloid Leukemia (AML) cells depend on SIRT5. I will employ genetic SIRT5 disruption and small molecule inhibitors to target SIRT5 in Acute Lymphoblastic Leukemia (ALL) cells and primary samples. This study aims to 1) determine the effects of SIRT5 inhibition on ALL in vitro and in vivo, and 2) identify SIRT5-regulated pathways and mechanisms underlying SIRT5 dependency in T-ALL.

AML risk stratification established by previous studies do not reflect survival outcomes observed in Black patients. Exome sequencing of 100 Black AML patients revealed the novel variants previously not affiliated with AML, including PHIP. Using multiomic patient sample captures and GEMMs, we will functionalize variants in PHIP and assess if they drive leukemogenesis and/or therapy resistance. The overall goal of this work is to implement inclusive genetic assessment tools for AML diagnosis.

The focus of my research is to evaluate the efficacy of and to unravel the molecular mechanisms underpinning a novel drug combination in AML targeting oncogenic protein translation and apoptosis. We will utilize genetic perturbation and other orthogonal approaches, including in vitro and ex vivo assays, and in vivo AML PDX models. The goal of my research is to transform the clinical management of AML patients, particularly for relapsed and difficult-to-treat subgroups.

NPM1-mutated leukemia is the most common AML in adult and characterized by upregulations of HOXA/B genes and MEIS1. Given the importance of oncogenic transcriptional program, I will determine regulatory molecules that cooperate with mutant NPM1 on chromatin by combining CRISPR/Cas9 screening approach in an innovative model system of endogenous transcription reporters with proteomics approach. This will facilitate identification of novel therapeutic targets specific for NPM1-mutated AML.

Altered B cell homeostasis plays a key role in the development of chronic graft-vs-host-disease (cGVHD) after hematopoietic stem cell transplantation (HCT). We hypothesize that the DNA sensor AIM2 plays a critical role in the fate of BCR-activated B cells after HCT. We will utilize novel mouse models to investigate AIM2-BCR modulation with clear translational implications in autoreactivity perpetuating cGVHD as well as functional humoral deficiency and vaccine hyporesponsiveness after HCT.

Nodular lymphocyte-predominant Hodgkin lymphoma is recognized as a disease entity in a spectrum of related diseases, including T-cell rich B-cell lymphoma. Although treatments are generally effective, a subset of patients suffers from lymphoma progression and aggressive disease transformations. Here, we propose to analyze clonal evolution of tumor cells and describe the spatial architecture of tissues with the goal to improve molecular classification and develop novel therapeutic approaches.

I want to understand how the t(1;22) translocation that involves a member of the m6A writer complex drives acute megakaryoblastic leukemia (AMKL). To identify culprit genes and pathways I will use multi-omics, including RNA, eCLIP, and TimeLapse Seq and proteomics. I will dissect the RBM15-MKL specific effects of a novel METTL3 inhibitor in primary murine and human AMKL in vitro and in vivo. My ultimate goal is to cure this rare infant leukemia by harnessing METTL3 inhibition.

Leukemia stem cells (LSCs) are highly heterogeneous populations and key contributors to AML progression. Here, I aim to employ heparan sulfate (HS) glycotyping to resolve LSC heterogeneity. Using complementary genetic and antibody-based approaches, I will delineate the functional roles of HS pathway during AML progression. The newer insights provided by these studies could potentially uncover novel LSC therapies and facilitate diverse training for me to become an independent leukemia researcher.

Overexpression of ID2 is a recurrent event in mature T-cell lymphoma (TCL), and its significance is yet to be established. We will use a multidisciplinary approach combining epigenetic, transcriptomic, and proteomic analysis in human and murine models to identify the mechanisms leading to ID2 overexpression and their effect on T-cell transformation. Our goal is to define the role of ID2 in lymphomagenesis and determine its potential as a novel therapeutic target in TCL.

T-cell mediated therapies are all impeded by the same cause- tumoral antigen (Ag) escape: rare Ag– cells in tumors survive the initial attack and lead to relapse. We recently took an innovative approach by enhancing T cells' ability to attack the Ag- cells during the initial treatment. That process is modular by pharmaceutical intervention.

The proposed project will analyze cryopreserved excisional B-NHL biopsies to identify possible pharmaceutical targets potentiating their 'vulnerability’.