# The role of PTPN11 and NPM1 mutations in acute myeloid leukemia development and therapy resistance

> **NIH NIH F30** · UNIVERSITY OF CINCINNATI · 2021 · $42,821

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute myeloid leukemia (AML) is a disease characterized by clonal expansion of myeloid cells with blocked
differentiation. Despite newly approved targeted therapies for AML, there is still a large subset of patients
whose disease progresses or does not respond to treatment. One group of patients that have demonstrated
resistance to targeted therapy (entospletinib, enasidenib, ivosidenib, and venetoclax) have protein tyrosine-
phosphatase non-receptor type 11 (PTPN11) mutations. The PTPN11 gene encodes for the phosphatase
Shp2, which regulates multiple signaling pathways including the RAS-MAPK pathway. PTPN11 mutations
(PTPN11+) commonly co-occur with mutations in the nucleophosmin (NPM1) gene. Our preliminary data
demonstrates that the co-association of PTPN11 and NPM1 mutations results in inferior outcomes for patients
treated with intensive chemotherapy. Intriguingly, we have seen that PTPN11+/NPM1+ patients rarely have
FLT3-ITD, an alteration that is well-known to worsen outcomes in NPM1+ AML. Because PTPN11 mutations
activate many downstream signaling pathways similar to FLT3-ITD, we hypothesize that the addition of
PTPN11 mutations to NPM1+ AML can clinically phenocopy NPM1+/FLT3-ITD AML in terms of adverse
outcomes and therapy resistance. Therefore, we have generated a novel transgenic Ptpn11E76K/Npm1cA mouse
model to study the development of AML and the resulting immunosuppressive phenotype. Using this model,
we will interrogate whether expanded myeloid cells from Ptpn11E76K/Npm1cA animals can initiate AML in
immunodeficient mice and confer resistance to chemotherapy. In addition, we will use modified AML cell lines
to study the mechanism of resistance, particularly the roles signaling pathways, antiapoptotic proteins, and
immunosuppression play. The knowledge gained will clarify the biology of PTPN11 mutations in AML and
provide the foundation to develop therapies that will be effective in patients with PTPN11+ AML.
This research will be completed by an MD/PhD student under the supervision of two leading translational
researchers in the field of AML. The MD/PhD program is well established at Ohio State, and cancer research
at the Comprehensive Cancer Center is robust and exceptionally strong. The training plan contains
opportunities for the development of critical thinking, scientific knowledge, technical expertise, clinical skills,
communication capabilities, and rigorous experimental design. Successful completion of the research proposal
and training plan will provide the skills necessary to become an independent researcher in the field of
hematology.

## Key facts

- **NIH application ID:** 10315877
- **Project number:** 1F30CA265281-01
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Sydney Fobare
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $42,821
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315877

## Citation

> US National Institutes of Health, RePORTER application 10315877, The role of PTPN11 and NPM1 mutations in acute myeloid leukemia development and therapy resistance (1F30CA265281-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10315877. Licensed CC0.

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