# Investigating the role of the JAK/STAT3 Pathway in Clonal Proliferation and Immune Dysfunction in Myelodysplastic Syndrome

> **NIH NIH K23** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $163,031

## Abstract

Project Summary
Myelodysplastic syndrome (MDS) is a heterogeneous group of pre-leukemic bone marrow failure disorders with
a yearly incidence of approximately 13,000 in the U.S. Approximately one third of MDS patients will go on to
develop acute myeloid leukemia (AML) with a dismal survival of 5-10%. Standard of care therapy only extends
life by a median of 9 months in those requiring treatment and there is no cure for the disease outside of stem
cell transplant. As the population ages, this disease will only become more common, thus there is an urgent
need for more effective treatments in MDS. MDS pathogenesis is marked by both clonal myeloid proliferation
and bone marrow immune dysfunction. In MDS bone marrow, a suppressive immune microenvironment
develops in response to initial inflammation and contributes to the proliferation of developing blasts, which are
free to grow unchecked by the immune system. In fact, myeloid-derived suppressor cells (MDSCs), myeloid cells
which are suppressive to T cell function, have been implicated in disease pathogenesis and progression. The
JAK/STAT3 pathway is critical in myeloid differentiation and is aberrantly activated in both myeloblasts and
MDSCs, both of which increase as MDS progresses. In order to better understand JAK/STAT3 signaling in MDS,
we will use single cell and functional genomic assays to profile STAT3 in primary patient samples, with particular
focus on myeloblasts and MDSCs – two separate but central cells types in leukemic progression of MDS. Given
our experience studying single cell phenotype and intracellular signaling in AML, we will adapt our methods to
study MDS, with particular focus on p-STAT3. An advantage of this approach is the ability to measure all cells
within a sample simultaneously and create single cell signaling profiles for each sample and in response to
inhibition. We propose three specific aims to investigate JAK/STAT3 signaling in MDS. In Aim I, the basal and
cytokine-induced responses of STAT3 signaling will be measured in banked MDS samples to understand the
role of STAT3 signaling in leukemic progression. Aim II will test functional and signaling responses to various
inhibitors of the JAK/STAT3 pathway. Finally, Aim III will determine the impact of standard therapy on JAK/STAT3
signaling and STAT3 targets in resistant MDS. Chromatin immunoprecipitation (ChIP-seq) will be used here in
order to profile the gene targets of STAT3 in MDS. These studies will significantly contribute to our basic
understanding of MDS and the therapeutic potential of the JAK/STAT3 pathway moving forward in this disease.
This proposal is ultimately designed to allow Dr. Ferrell to develop further skills in mass cytometry, phospho-
flow, immunology techniques and ChIP and to provide him with the critical mentoring and training necessary to
become an independent physician-scientist.

## Key facts

- **NIH application ID:** 9986011
- **Project number:** 5K23HL138291-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** PAUL B FERRELL
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $163,031
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986011

## Citation

> US National Institutes of Health, RePORTER application 9986011, Investigating the role of the JAK/STAT3 Pathway in Clonal Proliferation and Immune Dysfunction in Myelodysplastic Syndrome (5K23HL138291-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986011. Licensed CC0.

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