# The role of Pleckstrin-2 as a functional node in myeloid proliferation

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $486,783

## Abstract

PROJECT SUMMARY
Myeloproliferative neoplasms (MPNs) are a group of bone marrow diseases that show excessive myeloid cell
production with an increased risk of developing thrombosis and evolving to acute myeloid leukemia. V617F
driver mutation of JAK2 is one of the leading causes of MPNs. The discovery of this mutation led to the
development of JAK inhibitors to treat MPNs. However, JAK inhibitors are not curative. In addition, MPN
patients treated with JAK inhibitor often develop drug resistance and severe side effects due to the
indispensable roles of JAK2 in normal hematopoiesis. We have been studying new approaches to treat MPNs,
especially focusing on the downstream effectors of the JAK2 pathway. Our recently published studies funded
by the current R01 revealed that loss of Pleckstrin-2 (Plek2), a novel target of the JAK2-STAT5 pathway,
ameliorated JAK2V617F-induced myeloproliferative phenotypes, and more importantly reverted vascular
occlusions and lethality of the JAK2V617F MPN mouse model. Given the significance of Plek2 in MPN
pathogenesis, we have identified lead compounds of Plek2 small molecule inhibitors using in silico-based high-
throughput screenings and cell-based assays. Our novel unpublished preliminary data further reveal that Plek2
binds to several PI3K effectors and loss of Plek2 reduces Akt activation. Preliminary in vivo evidence also
demonstrates that Plek2 is critical for the PI3K-Akt pathway in that Plek2 knockout ameliorated
myeloproliferation and significantly extended the survival of Pten hematopoietic specific knockout mice. These
findings lead us to hypothesize that Plek2 functions as a central hub to connect the JAK2-STAT and the PI3K-
Akt pathways and promote myeloproliferation. To test this hypothesis and investigate the mechanism of
function of Plek2, we will use 1) in vitro biochemical and molecular studies to determine how Plek2 enhances
the PI3K-Akt signaling, 2) Pten hematopoietic specific knockout mouse model to reveal the functions of Plek2
in vivo, and 3) pre-clinical MPN models and MPN patient samples to establish the efficacy of Plek2 inhibitors.
Successful completion of this project will lead to novel insights into the role of Plek2 in the pathogenesis of
MPNs and lay the foundation for clinical trials using Plek2 inhibitors as single agents or in combination with
other compounds to treat MPNs.

## Key facts

- **NIH application ID:** 10432069
- **Project number:** 5R01HL150729-08
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Peng Ji
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $486,783
- **Award type:** 5
- **Project period:** 2020-07-09 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10432069

## Citation

> US National Institutes of Health, RePORTER application 10432069, The role of Pleckstrin-2 as a functional node in myeloid proliferation (5R01HL150729-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10432069. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*