# Functions of JARID2 in Normal and Neoplastic Hematopoiesis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $393,541

## Abstract

ABSTRACT
 Myeloproliferative neoplasms (MPNs) are clonal hematologic diseases characterized by the aberrant
proliferation of one or more myeloid lineages and progressive bone marrow fibrosis. More than 20,000 new
patients are diagnosed in the USA each year, and in a substantial portion of these patients disease
progression leads to transformation to secondary acute myeloid leukemia (sAML), a much more aggressive
and therapeutically-refractive disease. Patients who develop sAML have a poor prognosis with an average
survival time after transformation of less than five months. The clonal evolution of MPN to sAML is driven by
acquisition of additional co-operating genetic mutations. While advances in genome sequencing technology
have elucidated the genetic background of MPN, the contribution of specific genetic events to sAML
transformation is not well understood and do not seem to be explained by the individual genetic alterations that
characterize the disease. My laboratory has taken a particular interest in studying the mechanisms underlying
post-MPN sAML transformation because the disease invariably proves fatal, and any findings that improve the
diagnosis and treatment of these patients would represent a significant advance. One such event involves
chromosomal deletions of the short arm of chromosome 6, which contains the JARID2 gene. We show
conditional deletion of Jarid2 in mouse models accelerates development of MPN or leads to disease
progression to sAML depending on the context, and genetic inhibition of JARID2 in CD34+ cells from MPN
patients facilitates engraftment in immunodeficient mice and transmission of patient pathologies. Our
preliminary data establish JARID2 as a bona fide hematopoietic tumor suppressor. The motivation for this
proposal is to understand the mechanisms by which JARID2 exerts this function in MPN. We hypothesize that
JARID2 functions as a hematopoietic tumor suppressor by restricting self-renewal in lineage-committed
hematopoietic progenitor cells and restraining oncogenic JAK/STAT signaling. We will examine this through
the following Specific Aims;
  Determine the mechanisms by which JARID2 represses self-renewal in progenitors.
  Define mechanisms through which JARID2 functions as a tumor suppressor.
  Examine the unique requirement for JARID2 suppression in myelofibrosis.
 Understanding how JARID2 functions is critical for improving the clinical outcomes of sAML patients and
identifying patients at risk for transformation, while also serving as a more general paradigm for genetic
progression of MPN to sAML. In this proposal, we will leverage contemporary techniques with novel mouse
models to comprehensively understand the mechanisms of how JARID2 functions as a tumor suppressor, and
elucidate new precision medicine strategies for MPN and sAML patients.

## Key facts

- **NIH application ID:** 9948747
- **Project number:** 5R01HL147978-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Grant Anthony Challen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,541
- **Award type:** 5
- **Project period:** 2019-06-10 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948747

## Citation

> US National Institutes of Health, RePORTER application 9948747, Functions of JARID2 in Normal and Neoplastic Hematopoiesis (5R01HL147978-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9948747. Licensed CC0.

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