# MUTANT AND WILD TYPE WT1 IN AML

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2020 · $137,729

## Abstract

Project summary/abstract
This proposal describes a 5-year career development program designed to support an academic, physician-
scientist career. The proposed research project will capitalize on the expertise and resources available at
Washington University in St. Louis, which has a long tradition of developing physician-scientists. Dr. Timothy
Ley, an expert in myeloid development and cancer genomics and a recipient of the American Society of
Hematology Mentor Award, will serve as the research mentor. The ultimate goal of the candidate is to be an
independent investigator in an academic medical center, studying normal and malignant hematopoiesis and
taking care of patients with hematologic diseases.
The experiments outlined in this application aim to clarify the role of wild type and mutant WT1 in Acute
myeloid leukemia (AML) progression, with the goal to create new therapeutic approaches for this disease.
Wilms tumor 1 (WT1) is a zinc-finger family transcription factor that is highly expressed in AML cells compared
to normal hematopoietic progenitor cells, consistent with a possible role in promoting AML development and
leading to considerable clinical interest in WT1 as a therapeutic target. Paradoxically, loss-of-function
mutations in WT1 are also found in a subset of AML cases, raising the possibility that WT1 may promote or
inhibit development of leukemia depending on the molecular context. Our lab recently performed preliminary
studies suggesting that when co-occurring with the PML-RARA fusion, WT1 inhibits leukemic progression and
self-renewal in a mouse model, suggesting that in this setting WT1 may prevent or delay leukemic progression.
To reconcile the seemingly contradictory role of WT1 in AML progression we developed the following
hypothesis to be tested in this proposal: WT1 expression is triggered in hematopoietic progenitors as a
defensive response to AML-associated driver mutations. While fully transformed AML has developed means
to overcome this inhibition, subsequent loss-of function mutations in WT1 provide a growth advantage to
mutant subclones. Consistent with this hypothesis, we recently found that WT1 mRNA is induced 10-fold in
CD34+ cells that have been transduced with several canonical AML-associated fusion genes. In this proposal,
we will extend these observations to test whether overexpression or loss-of-function of WT1 can cooperate
with these AML-associated mutations in mouse and human systems.

## Key facts

- **NIH application ID:** 9985595
- **Project number:** 5K08CA222630-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MATTHEW CHRISTOPHER
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $137,729
- **Award type:** 5
- **Project period:** 2017-09-21 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985595

## Citation

> US National Institutes of Health, RePORTER application 9985595, MUTANT AND WILD TYPE WT1 IN AML (5K08CA222630-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9985595. Licensed CC0.

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