# MPN-inducing mutations as biomarkers of synthetic lethality

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2024 · $406,919

## Abstract

Myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV), essential thrombocythemia
(ET), and primary myelofibrosis (PMF) often carry JAK2(V617F), MPL(W515L) and mutations in
calreticulin (CALRmut). These aberrations may be accompanied by mutations in TET2, ASXL1,
DNMT3A, EZH2, and other genes further complicating utilization of MPNs genetic/epigenetic
signatures as potential biomarkers for therapeutic decisions.
Current treatment options for MPNs include myelosuppressive therapy in the form of
hydroxyurea and JAK1/2 inhibitor QAK1/2i) ruxolitinib. MPNs can have prolonged chronic phases,
but may eventually accelerate and transform into a secondary acute myeloid leukemia that is
ultimately fatal. Therefore, it is imperative to generate new therapies that alone or in combination
with already approved drugs could potentially extend the complete remission time and/or be used
in patients which progressed to the malignant stage. Since all 3 "main" mutations [JAK2 (V617F),
CALR(del52), and MPL(W515L)] were found in MPN stem cells (MPNSCs) these cells must be
eliminated in order to improve therapeutic outcome. Unfortunately, the potential therapeutic
approaches against MPNSCs are limited.
MPN cells, including MPNSCs accumulate potentially lethal DNA double-strand breaks (DSBs),
which are repaired by two major mechanisms, BRCA-mediated homologous recombination (HR) and
DNA-PK -mediated non-homologous end-joining (D-NHEJ). HR and D-NHEJ repair DSBs in
proliferating cells and D-NHEJ plays a major role in quiescent cells. PARP1 -dependent back-up NHEJ
(B-NHEJ) serves as back-up in both proliferating and quiescent cells.
Cancer-specific defects in DSB repair create the opportunity to employ synthetic lethality, e.g.
elimination of BRCA1/2-mutated cancer cells by PARP1 inhibitor (PARP1i). However, BRCA1/2
mutations are rare in MPNs. We hypothesize that MPN-inducing mutations are prognostic
biomarkers of therapeutic synthetic lethality triggered by DNA repair inhibitors.
We will determine if specific MPN-inducing mutation(s) (biomarkers) predispose quiescent
and/or proliferating MPN stem and progenitor cells from individual patients to PARP1i-induced
synthetic lethality combined with the inhibitors of HR and D-NHEJ (Aim #1) or with JAK2i (Aim #2).
We will also employ murine knockin/knockout models of MPNs and primary MPN xenografts in
humanized immunodeficient mice to determine if DNA repair inhibitors and/or JAK2i exert anti-MPN
synthetic lethal effect in pre-clinical settings (Aim #3).

## Key facts

- **NIH application ID:** 10849882
- **Project number:** 5R01CA247707-05
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** TOMASZ SKORSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $406,919
- **Award type:** 5
- **Project period:** 2020-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849882

## Citation

> US National Institutes of Health, RePORTER application 10849882, MPN-inducing mutations as biomarkers of synthetic lethality (5R01CA247707-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10849882. Licensed CC0.

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