# Eradicating leukemic stem cells in juvenile myelomonocytic leukemia

> **NIH NIH R21** · EMORY UNIVERSITY · 2023 · $182,909

## Abstract

Project Summary
Juvenile myelomonocytic leukemia (JMML), a clonal hematological malignancy of early childhood, has limited
therapeutic options. While the current standard of care for patients with JMML relies on allogeneic stem cell
transplant, relapse remains the main cause of treatment failure, most likely due to the persistence of leukemic
stem cells (LSCs), a small population of self-renewing precursor cells that gives rise to the bulk of tumor cells.
This reservoir of tumor cells is responsible for the long-term maintenance of leukemia growth and is also a major
source of drug resistance. It remains a critical challenge to develop effective therapeutics to eradicate these
tumor initiating cells. A novel treatment approach focused on the unique characteristics and vulnerabilities of
LSCs is needed in order to address this problem. JMML is associated with genetic mutations in the signaling
proteins involved in the Ras pathway, among which the protein tyrosine phosphatase Ptpn11 (Shp2), a positive
regulator of Ras signaling, is most frequently mutated (heterozygous). These mutations cause greatly increased
catalytic activity of Shp2, and JMML patients with Ptpn11 mutations have the worst prognosis in all subtypes of
JMML. We created a line of conditional knock-in mice with the Ptpn11E76K mutation, the most common mutation
found in JMML. Induction of the Ptpn11E76K/+ mutation in the hematopoietic system (Ptpn11E76K/+/Mx1-Cre+ mice)
resulted in JMML-like myeloproliferative neoplasm (MPN) with full penetrance, suggesting a causative role of this
mutation in the pathogenesis of JMML. With this unique mouse model, we have recently discovered that while
the Ras/Erk signaling pathway was aberrantly enhanced, Stat3 activity as reflected by tyrosine phosphorylation
(Tyr705) decreased by ~70% in Ptpn11E76K/+ mutant stem cells (referred to as LSCs since they could reproduce
the same hematological malignancy in transplants) compared to that in wild-type (Ptpn11+/+/Mx1-Cre+) control
stem cells. The decrease in Stat3 activity was apparently caused by the accelerated dephosphorylation of Stat3
by the hyperactive Shp2 E76K mutant because Stat3 is one of Shp2 substrate proteins. Importantly, Ptpn11E76K/+
LSCs appear to rely on Stat3 for self-renewal and maintenance - the deletion of Stat3 dramatically decreased the
LSC pool in Ptpn11E76K/+/Mx1-Cre+/Stat3fl/fl double mutant mice. Consequently, these double mutant mice died
rapidly, while none of Ptpn11E76K/+/Mx1-Cre+/Stat3+/+ or Ptpn11+/+/Mx1-Cre+/Stat3fl/fl single mutant mice did. The
synthetic lethality induced by Stat3 deletion in Ptpn11 E76K mutant stem cells raises an intriguing possibility, that
is, diminished Stat3 activity is an Achilles' heel of Ptpn11 mutated (Shp2 hyperactivated) LSCs, making them
vulnerable to pharmacological inhibition of Stat3. We plan to test this hypothesis and accomplish the objective of
this proposal by pursuing the following two aims. 1) To define the role of Stat3 in maintena...

## Key facts

- **NIH application ID:** 10722045
- **Project number:** 1R21CA282579-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** CHENG-KUI QU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $182,909
- **Award type:** 1
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10722045

## Citation

> US National Institutes of Health, RePORTER application 10722045, Eradicating leukemic stem cells in juvenile myelomonocytic leukemia (1R21CA282579-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10722045. Licensed CC0.

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