# Molecular characterization and targeting of NT5C2 mutations in acute lymphoblastic leukemia

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $383,193

## Abstract

Project Summary/Abstract
Despite intensive chemotherapy, 20% of pediatric and over 50% of adult acute lymphoblastic leukemia (ALL)
ALL patients fail to achieve a complete remission or relapse after intensified chemotherapy, making relapse
and resistance to therapy the most significant challenge in the treatment of this disease. This project seeks to
dissect the structure and function of NT5C2, a cytosolic nucleotidase activated by gain of function mutations in
about 45% of early relapse B-precursor ALL and 35% of early relapse T-ALL cases. NT5C2 mutations are
characteristically associated with early relapse and progression under therapy and confer resistance to 6-
mercaptopurine chemotherapy in vitro and in vivo. Our central hypothesis is that activating mutations in
NT5C2 lock the NT5C2 protein in an active state either by forcing a constitutively active configuration similar to
that induced by allosteric activators or via disruption of intramolecular switch off mechanisms responsible for
returning the enzyme to its resting inactive state after activation. In this context, we will perform detailed
structure-function analysis of NT5C2 mutant proteins to guide the development of new therapies for the
treatment of relapse and refractory ALL.

## Key facts

- **NIH application ID:** 9983754
- **Project number:** 5R01CA216981-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Adolfo A. Ferrando
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,193
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983754

## Citation

> US National Institutes of Health, RePORTER application 9983754, Molecular characterization and targeting of NT5C2 mutations in acute lymphoblastic leukemia (5R01CA216981-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983754. Licensed CC0.

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