# Targeting Novel Pathways in JMML

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $542,416

## Abstract

PROJECT SUMMARY/ABSTRACT
Juvenile myelomonocytic leukemia (JMML) is a common myeloproliferative neoplasm (MPN) in childhood.
JMML is characterized as being Ras-driven due to mutations in NF1, CBL, KRAS, NRAS, or PTPN11, and cells
from JMML patients show hypersensitivity to GM-CSF. Chemotherapeutic agents are mostly ineffective in JMML,
and the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). A common clinical
picture in JMML is that it presents as a hyperinflammatory syndrome, and is often difficult to distinguish from
viral infections. Thus, a component of JMML is associated with hyperinflammatory state and hyperactive innate
immune cells. Further, unlike other MPNs, JMML rarely progresses to blast crisis; rather, mortality is due to
extramedullary myeloid cell expansion leading to organ failure. Importantly, following allogeneic HSCT, 50% of
patients succumb to leukemia relapse, implicating a role for bone marrow microenvironment (BME) in JMML
development and progression. The hyperinflammatory nature of JMML may damage the BME, altering the
expansion of normal donor cells following transplant, permitting residual leukemia cells to outcompete the normal
graft, and leading to relapse. Utilizing mouse models of JMML, we demonstrate relapse in mice bearing PTPN11
mutations, we show altered composition of the BME in PTPN11 bearing mice and provide evidence that JMML
patients that have a higher neutrophil count at the time of HSCT are more likely to relapse. These data combined
with previous studies demonstrating hyperactive and inflamed neutrophils due to PTPN11 mutations suggests
that these cells may contribute to relapse. We will examine this in detail. We have been analyzing multiple RNA
sequencing datasets for lncRNAs that are differentially expressed in JMML. In doing so, we identified several
novel lncRNAs whose expression is differentially regulated. We will examine how one of these lncRNAs
contributes to JMML pathogenesis. We have recently shown that PI3K catalytic subunit p110δ contributes to
both Akt and Erk hyperactivation, and promotes PTPN11-induced GM-CSF hypersensitivity and
hyperproliferation, thus partially contributing to the progression of JMML. Given the lack of complete rescue by
loss of p110δ in PTPN11-induced JMML, we sought out putative tyrosine kinases that signal together with p110δ
in the PI3K-Akt signaling pathway that must be targeted for optimal JMML therapy. We present preliminary data
demonstrating that Bruton's Tyrosine Kinase (BTK) inhibition collaborates with PI3K p110δ inhibition to reduce
the activation of Akt and Erk in PTPN11-expressing cells. We will study the mechanism behind this cooperation.
Overall, the proposed Aims will shed novel insight into JMML development and pathogenesis as well as
identification of novel therapeutic targets.

## Key facts

- **NIH application ID:** 10324564
- **Project number:** 5R01HL146137-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Reuben Kapur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $542,416
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10324564

## Citation

> US National Institutes of Health, RePORTER application 10324564, Targeting Novel Pathways in JMML (5R01HL146137-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10324564. Licensed CC0.

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