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

> **NIH NIH R35** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $1,077,000

## Abstract

ABSTRACT
Acute lymphoblastic leukemia (ALL) is a leading cause of cancer death in children. The goal of my research is
to use integrated genomic and epigenomic profiling to define the genomic alterations that drive
leukemogenesis and treatment failure in ALL, and to use this information to develop mouse models to translate
these discoveries to innovative therapeutic approaches. My research program has revised the molecular
taxonomy of ALL, identified constellations of genetic mutations that define subtypes of ALL, has dissected the
genetic basis of clonal evolution, identified new targets for therapeutic intervention, notably with tyrosine kinase
inhibitors, and has established several new engineered models of high-risk B-progenitor ALL. Recent
advances include identification of a high frequency of mutations in epigenetic regulators at relapse in ALL, and
demonstrating that specific genomic alterations perturb the interaction of leukemic cells with the
microenvironment, resulting in resistance to therapy. This research proposal will determine the mechanistic
basis by which genetic lesions present at diagnosis, or enriched at relapse, determine resistance to therapy,
and exploit these for therapeutic intervention. Research goals are (1) to identify the constellations of genomic
and epigenomic alterations that characterize each subtype of ALL across the age spectrum, and identifying
those alterations that cause treatment failure. This involves genome and transcriptome sequencing of
childhood and adult ALL, and integrated whole genome, whole genome bisulfite, transcriptome and chromatin
mark sequencing of a cohort of 100 ALL cases, including matched samples obtained at diagnosis and relapse
and corresponding xenografts. This is essential to identify all coding and non-coding mutations driving disease,
to systematically examine the effect of genetic alterations on chromatin remodeling, and to guide the
development and interpretation of mouse models of ALL. (2) To perform multiplexed loss-of-function screens
using expression of founding oncogenic fusions, coupled with RNA interference and genome editing to dissect
the interaction of polygenic alterations in leukemogenesis. (3) To use gene-specific and loss-of-function
screens to examine the role of epigenomic alterations in ALL relapse. These include detailed characterization
of Crebbp knockin models of ALL, and RNAi/CRISPR/Cas9 screens targeting over 700 chromatin modifier
genes in B-ALL leukemia models. Enriched hits, and their effects on chromatin modeling and transcriptional
regulation will be compared to data from human leukemic cells; and the resulting models used to test the effect
of epigenetic modifying agents on modulating drug resistance. (4) To use mouse models of B-ALL to dissect
the role of cellular mislocalization and “hijacking” of the bone marrow niche and the role of this phenomenon in
drug resistance. Together, these approaches provide a comprehensive strategy to fully define the ge...

## Key facts

- **NIH application ID:** 10085207
- **Project number:** 5R35CA197695-05
- **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:** 2021
- **Award amount:** $1,077,000
- **Award type:** 5
- **Project period:** 2017-01-19 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085207

## Citation

> US National Institutes of Health, RePORTER application 10085207, Translating genomic discoveries to improved outcomes for high risk acute leukemia (5R35CA197695-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085207. Licensed CC0.

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