# STAT5 in B cell Acute Lymphoblastic Leukemia

> **NIH NIH F30** · UNIVERSITY OF MINNESOTA · 2021 · $50,609

## Abstract

Project Abstract
Progenitor B cell acute lymphoblastic leukemia (B-ALL) is the most common form of childhood cancer. New
therapies have substantially improved the prognosis of this type of cancer, yet relapsed B-ALL remains a
leading cause of death in children and young adults. Thus, B-ALL remains a significant health challenge.
Currently, activation of the JAK/STAT5 pathway is strongly implicated in the development of B-ALL. Likewise,
genes encoding a network of transcription factors required for B cell development, including IKZF1, PAX5, and
EBF1, are frequently expressed at lower levels in B-ALL due to deletions in one of the alleles encoding these
transcription factors. Our lab has shown that STAT5 activation cooperates with defects in the pre-BCR
signaling pathway, including PAX5, EBF1, PU.1, IRF4, and IKAROS (collectively referred to as PEPII factors
hereafter) to initiate transformation. Therefore, these findings demonstrated that proper balance between
STAT5 activation and PEPII factors is important for entraining normal B cell differentiation and preventing B
cell transformation. One key question that emerges from these results is how STAT5 activation can alter target
gene expression. Our data suggests that active phosphorylated STAT5 can bind to target genes and both
activate key oncogenes while repressing tumor suppressor genes. However, the mechanism by which this
occurs remains unclear. Based on previous studies and preliminary data, STAT5 can associate with
co-activators, such as EP300 and CREBBP, and with co-repressors, such as NCOR1 and NCOR2. I hereby
propose that the recruitment of EP300 but not CREBBP is critical for STAT5 to induce transcription of
key oncogenes. I further propose that the interaction of STAT5 with the NCOR1 and NCOR2 repressor
complex is required for STAT5- dependent repression of tumor suppressor genes. Thus, my central
hypothesis is that a proper STAT5 transcriptional network is required for promoting normal B cell
development and that perturbation of this network can lead to B cell transformation. These hypotheses
will be tested in the following two specific aims (1) Establish the mechanism by which STAT5 regulates the
transcription of key oncogenes, and (2) Establish how STAT5 represses transcription of key tumor suppressor
genes in progenitor B cell leukemia. The completion of these aims will further advance our understanding of
how STAT5 both activates and represses transcription and how subsequent perturbation of these functions
can lead to transformation in B-ALL.

## Key facts

- **NIH application ID:** 10218099
- **Project number:** 5F30CA232399-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Robin D. Lee
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $50,609
- **Award type:** 5
- **Project period:** 2018-07-19 → 2023-07-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218099

## Citation

> US National Institutes of Health, RePORTER application 10218099, STAT5 in B cell Acute Lymphoblastic Leukemia (5F30CA232399-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10218099. Licensed CC0.

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