# Elucidating Critical Dependencies Underlying Therapeutic Evasion in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2024 · $184,541

## Abstract

PROJECT SUMMARY/ABSTRACT
 This mentored career development award proposal will facilitate my career goal to become an
independent translational researcher using advances in experimental genomics and bioinformatics to develop
improved precision medicine therapies for children with difficult-to-cure cancers. During the 5-year training period
I plan to acquire critical skills in computational biology and pursue additional didactic training in transcriptional
regulation, death pathways, single cell analyses, and early-phase clinical trial design. The proposed studies and
training will be completed under the co-mentorship of Dr. Kai Tan and Dr. Sarah Tasian, both internationally
recognized leaders with complementary expertise in systems and single cell biology and in translational leukemia
research, respectively. My multi-disciplinary Advisory Committee is composed of world-renowned scientists who
have extensive mentoring experience and diverse expertise, including Drs. Chi Dang, Nancy Speck, John Maris,
and Xiaolu Yang. The scientific proposal is aimed at elucidating critical dependencies that synergize with kinase
pathway oncogene addiction in Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL), a
kinase-driven leukemia with dismal outcomes. Ph-like ALL comprises 15-40% of childhood and adult ALL cases
and is associated with extremely high relapse rates and very poor overall survival. We observed in preclinical
Ph-like ALL models that treatment with the JAK inhibitor ruxolitinib has incomplete efficacy and also resulted in
global gene expression changes. Thus, combination therapy approaches that effectively target key therapeutic
escape mechanisms are needed. Additionally, single-cell variability in Ph-like ALL that may drive targeted
therapy resistance is unknown. I hypothesize that ruxolitinib treatment in JAK/STAT pathway-altered Ph-like ALL
cells leads to rewiring of the gene regulatory network at transcriptional and epigenetic levels (likely mediated by
c-MYC), resulting in cell cycle arrest and apoptotic priming amenable to co-targeting. I propose in Aim 1 to model
patient leukemia reponse to kinase inhibition in vivo and to identify transcriptional regulatory network changes
during chronic ruxolitinib treatment with subsequent functional validation. This represents an unbiased approach
to identifying unknown oncogenic dependencies. In Aim 2, I will use single-cell techniques to examine genetic
and non-genetic sub-populational changes during targeted drug perturbation over time, then to characterize and
target resistant cell states. These studies will form the basis for developing rational combinations of molecularly
targeted therapies to improve cure rates for patients with Ph-like ALL. In summary, I will benefit from the
exceptional interdisciplinary expertise and track-record of my mentors and Advisory Committee, as well as the
rich intellectual environment and scientific resources available at CHOP and Penn, which pro...

## Key facts

- **NIH application ID:** 10986579
- **Project number:** 7K08CA273531-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Yang-Yang Ding
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $184,541
- **Award type:** 7
- **Project period:** 2024-01-05 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10986579

## Citation

> US National Institutes of Health, RePORTER application 10986579, Elucidating Critical Dependencies Underlying Therapeutic Evasion in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia (7K08CA273531-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10986579. Licensed CC0.

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