# Define the Role of POT1 Mutation in Genome Instability and Cancer

> **NIH NIH U01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $416,273

## Abstract

Project Summary
The goal of this proposal is to investigate the mechanism by which alteration in the telomere
binding protein POT1 results in tumorigenesis. Mutations in POT1 (>100) have been associated
with several types of human cancers such as chronic lymphocytic leukemia (CLL), cutaneous T
cell lymphomas (CTCL), mantel cell lymphomas, parathyroid adenomas, gliomas, and
melanomas. Our preliminary data indicate that perturbations in POT1 lead to replication stress at
telomeres and telomere dysfunction. Moreover, we have shown that inhibition of POT1 in the
common lymphoid progenitor cells (CLPs) promotes the formation of thymic lymphomas in mice.
Here we will test our hypothesis that POT1 mutations trigger telomere replication stress which in
turn leads to genome instability and cancer development. In addition, we will address the
mechanism that enables cancer cells with POT1 mutations to bypass telomere replication stress
and proliferate indefinitely. Lastly, we will develop a genetic screen to interrogate POT1 mutations
in vivo and identify driver-mutations. In conclusion, our study will provide an important step
towards identifying novel and effective therapeutic targets to treat an increasing number of cancer
patients with POT1 mutations.

## Key facts

- **NIH application ID:** 10485916
- **Project number:** 5U01CA231019-06
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Agnel Sfeir
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $416,273
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485916

## Citation

> US National Institutes of Health, RePORTER application 10485916, Define the Role of POT1 Mutation in Genome Instability and Cancer (5U01CA231019-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10485916. Licensed CC0.

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