# Characterizing the pathogenesis and targeted therapeutics of Wilms' Tumor 1 (WT1) mutations in AML

> **NIH NIH K99** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $102,142

## Abstract

PROJECT SUMMARY/ABSTRACT
Dr. Haijiao Zhang has been training as a medical student for 7 years with a focus on hematological
malignancies and as a researcher for 6 years in the field of characterizing oncogene and drug resistance
mechanisms. Her research has led to 8 published manuscripts and 4 other manuscripts in submission
/preparation. The theme of Dr. Zhang's research involves systematic characterization of leukemia oncogenes
and understanding leukemia drug resistance mechanisms. She has characterized 4 distinct mechanisms of
CSF3R mutations and diverse mechanisms associated with drug resistance to the FLT3 inhibitor crenolanib.
The WT1 (Wilms' tumor 1) gene encodes a transcription factor with C-terminal zinc-finger domains, whereas
the N-terminal part contains domains that mediate receptor dimerization, RNA recognition, and transcriptional
regulation. WT1 mutations are present in approximately 10–15% of AML and are associated with
chemotherapy resistance and disease relapse. WT1 mutations are frameshift mutations or substitutions across
all structural domains, predominantly in exons 7 and 9. The pathogenesis mediated by loss-of-function of WT1
zinc finger domain mutations has been studied; however very little is known about the oncogenic potential,
drug sensitivity, and the structural basis of mutations residing in other domains of WT1. In the current proposal,
Dr. Zhang will evaluate the functional consequences of these mutations and characterize the mechanisms
associated with the growth/survival advantage and a higher propensity for chemotherapy resistance of WT1
mutations. She also aims to identify therapeutics with enhanced efficacy in the WT1 mutant setting. Using ex
vivo inhibitor screening on primary leukemia patient samples, she has determined that inhibitors of BCL2 and
RAF/ERK pathways demonstrated higher efficacy against WT1 mutant samples compared with controls. She
will validate these findings using NRG mouse model. Finally, she will investigate the phenotypic, mechanistic,
and therapeutics targeting WT1 combinatorial mutation.
Dr. Zhang's long-term career goals include the establishment of an independent research lab focusing on
systematic characterization of oncogenic mutations and chemotherapy resistance to better predict the clinical
relevance of mutations and identify novel therapeutics to circumvent chemotherapy resistance.
During the mentored phase, she will continue to receive excellent mentorship from Dr. Jeffrey Tyner, an expert
on functional genomics and targeted therapy. She will receive co-mentorship from Dr. Ravi Majeti, an expert in
leukemia stem cell biology, CRISPR editing, and high-fidelity xenotransplantation mouse models, which she
will use in the current project. The proposed research will also be enhanced by guidance from Dr. Brian Druker,
a pioneer in translational medicine and targeted therapies for cancer; and Dr. Shannon McWeeney who will
provide guidance in bioinformatics analyses. Additionally, Dr. Ty...

## Key facts

- **NIH application ID:** 9898335
- **Project number:** 5K99CA237630-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Haijiao Zhang
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $102,142
- **Award type:** 5
- **Project period:** 2019-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898335

## Citation

> US National Institutes of Health, RePORTER application 9898335, Characterizing the pathogenesis and targeted therapeutics of Wilms' Tumor 1 (WT1) mutations in AML (5K99CA237630-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898335. Licensed CC0.

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