# Translating genomic discoveries to improved outcomes for high risk acute leukemia

> **NIH NIH R35** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $6,840

## Abstract

ABSTRACT
Acute leukemia is a leading cause of death in the young. The goal of my research program is to identify the
genomic drivers of leukemogenesis and treatment failure, and through experimental modeling gain mechanistic
insight to enable the development of new diagnostic and therapeutic approaches, and ultimately improve cure
rates for this disease. In the last project period, I identified multiple subtypes of leukemia that led to a revision of
the molecular taxonomy of acute lymphoblastic and lineage ambiguous leukemia; I defined the relationship of
genomic variegation and clonal evolution in leukemia; I demonstrated the role of liquid-liquid phase separation
in leukemogenesis; and I developed new therapeutic approaches using targeted protein degradation directed at
intractable drivers of high-risk leukemia. In this proposal, the original overarching goal remains unchanged, but
my research program will address several conceptually new areas of research that have been stimulated by my
prior discoveries. These include (1) defining the mechanism by which enhancer deregulation drives
leukemogenesis in T-lineage ALL; (2) investigating how concomitant LMO2-activating and STAG2-inactivating
alterations perturb chromatin state to drive leukemogenesis, and how this may be exploited for therapeutic
benefit; (3) elucidating how BCL11B deregulation primes primitive hematopoietic cells for lineage ambiguous
leukemia; (4) determining how fusion oncoprotein-driven liquid-liquid phase separation (LLPS) drives chromatin
and transcriptional deregulation in leukemogenesis, and how this may be targeted for therapeutic benefit; and
(5) developing molecular glue-based targeted protein degradation strategies to improve cure rates for childhood
leukemia. These research areas explore central questions in childhood and adult leukemia, including the
mechanisms by which enhancer hijacking/deregulation events drive leukemogenesis, the basis of cell lineage
ambiguity in lineage ambiguous leukemia, the mechanistic role of LLPS in leukemogenesis, and the efficacy of
innovative therapeutic approaches to degrade intractable drivers of acute leukemia. To achieve these goals I will
use innovative experimental approaches including novel engineered mouse models, single cell barcoding and
lineage tracing, multiomic gene expression-chromatin profiling, LLPS-condensate profiling, and exploitation of a
unique small molecule library of molecular glues. This research program will be facilitated by collaborations with
colleagues with expertise in these approaches. Collectively, these approaches will yield fundamental mechanistic
insight and therapeutic advances that will improve cures for currently intractable high risk leukemias.

## Key facts

- **NIH application ID:** 11064686
- **Project number:** 3R35CA197695-09S1
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Charles G Mullighan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $6,840
- **Award type:** 3
- **Project period:** 2017-01-19 → 2030-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11064686

## Citation

> US National Institutes of Health, RePORTER application 11064686, Translating genomic discoveries to improved outcomes for high risk acute leukemia (3R35CA197695-09S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11064686. Licensed CC0.

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