# The Role of PTPN11 in Myelofibrosis

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $399,195

## Abstract

Title: The Role of PTPN11 in Myelofibrosis
Project Summary/Abstract
Myelofibrosis (MF) is the most severe form of myeloproliferative neoplasm (MPN), characterized by deposition
of fibrous tissues in the bone marrow, abnormal megakaryopoiesis, and extramedullary hematopoiesis. The
median survival for patients with MF is ~5 years. A somatic activating V617F mutation in the Janus Kinase 2
(JAK2V617F) has been found in 50-60% patients with MF. Additional mutations in the genes encoding
thrombopoietin receptor (MPL) and calreticulin (CALR) have been found in MF but at a lower frequency than
JAK2V617F. Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved for treatment of MF. Although Ruxolitinib
can reduce splenomegaly, it failed to produce disease remission or prevent fibrosis in patients with MPN/MF. It
has already become clear that current chemotherapies including JAK2 inhibitors are not sufficient to cure
MPN/MF. So, there is a critical need to identify new therapeutic target(s) and develop novel targeted therapies
for MF. In preliminary studies, we have identified protein tyrosine phosphatase PTPN11 as a potential
therapeutic target in MF. We have found that PTPN11 is constitutively phosphorylated in mouse and human
MPN hematopoietic cells/progenitors. Knockdown of PTPN11 significantly inhibits proliferation of cells
expressing JAK2V617F. In preliminary studies, using conditional PTPN11 knockout and JAK2V617F knock-in
mice, we have observed that deletion of PTPN11 prevents the development of PV and markedly inhibits
myelofibrosis. We also have observed that pharmacologic inhibition of PTPN11 significantly inhibits the growth
of JAK2V617F-positive MPN cells and markedly reduces the bone marrow fibrosis in JAK2V617F knock-in
mice. So, we hypothesize that PTPN11 may play an important role in the pathogenesis of MF, and inhibition of
PTPN11 might be useful for treatment of MPN/MF. To test our hypothesis, we have proposed three specific
aims. In Aim 1, we will investigate the role of PTPN11 in the pathogenesis of myelofibrosis (MF). In Aim 2, we
will determine the efficacy of PTPN11 inhibition against MPN cells/progenitors and animal models of MPN/MF.
In Aim 3, we will determine the mechanism by which PTPN11 depletion or inhibition blocks the development/
progression of MPN/MF. Our proposed studies will provide the first demonstration that PTPN11 plays an
important role in the pathogenesis of MF and inhibition of PTPN11 is a novel therapeutic approach in MF. We
will also have mechanistic understanding on how PTPN11 contributes to the development of MF. Results from
these studies should lead to the design of a Phase I/II clinical trial involving PTPN11 inhibitor for treatment of
MPN/MF.

## Key facts

- **NIH application ID:** 9864941
- **Project number:** 1R01HL149893-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Golam Mohi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,195
- **Award type:** 1
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864941

## Citation

> US National Institutes of Health, RePORTER application 9864941, The Role of PTPN11 in Myelofibrosis (1R01HL149893-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9864941. Licensed CC0.

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