# Defining novel genetic dependencies in spliceosome mutant leukemia

> **NIH NIH R00** · FRED HUTCHINSON CANCER CENTER · 2022 · $77,497

## Abstract

PROJECT SUMMARY AND ABSTRACT
CANDIDATE: I am a postdoctoral research fellow in Dr. Omar Abdel-Wahab's laboratory at the Human
Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. My current research
focuses on pathogenesis and therapy of splicing factor mutations in leukemias. We previously demonstrated
that spliceosome-mutant leukemias are more susceptible to splicing modulatory compounds than wildtype
leukemia. Extending from these observations, we are now systematically defining previously unknown genetic
dependencies in spliceosome mutant leukemias to identify actionable targets that can be translated clinically.
The proposed research will form a solid platform from which I can establish my own research group by the end
of the K99 Award period. My long-term career goal is to establish a research program focusing on the
molecular regulation of normal and malignant hematopoiesis, with a strong commitment to translate basic
scientific discoveries into the clinic. I have developed a focused training plan to ensure my success to
becoming an independent investigator: (1) broaden my scientific scope and experimental skillsets; (2) enhance
leadership potential and professional development; (3) establish an independent committee to oversee on my
training progress, and (4) transition into tenure-track research independence in the R00 phase.
RESEARCH: Acquired mutations in genes encoding the RNA splicing factors SF3B1, SRSF2 and U2AF1
represent the most prevalent class of genetic alterations in leukemias. These mutations occur as heterozygous
point mutations at specific hot-spots and confer functional alterations in RNA splicing. With the exception of
MDS-RARS patients, spliceosome mutations in myeloid leukemias are correlated with poor clinical outcome.
Although we have previously shown that spliceosome-mutant leukemias are more susceptible to
pharmacologic modulation of splicing, additional vulnerabilities in mutant leukemias are unknown. We aim to
define the genetic dependencies unique to spliceosome mutant leukemias. The Specific Aims are: (1) identify
the mechanistic basis for mutual exclusivity of spliceosome mutations in leukemias, (2) define novel genetic
dependencies specific to spliceosome mutant leukemias, and (3) investigate the role of mutant SF3B1-
mediated MAP3K7 mis-splicing in the pathogenesis and therapy of leukemia.
ENVIRONMENT: As a member of the Abdel-Wahab laboratory, we are part of the Human Oncology and
Pathogenesis Program (HOPP) at MSKCC, a department that specializes in mechanism-based research to
advance clinical translation. Under the leadership of Dr. Charles Sawyers, HOPP is known for its highly
collaborative environment to facilitate translational research efforts such as those proposed in this application.

## Key facts

- **NIH application ID:** 10601425
- **Project number:** 6R00CA218896-06
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Stanley Chun-Wei Lee
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $77,497
- **Award type:** 6
- **Project period:** 2019-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10601425

## Citation

> US National Institutes of Health, RePORTER application 10601425, Defining novel genetic dependencies in spliceosome mutant leukemia (6R00CA218896-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10601425. Licensed CC0.

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