NFAT transcription factors are essential and redundant actors for leukemia initiating potential in T-cell acute lymphoblastic leukemia
Open Access
- 7 July 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 16 (7), e0254184
- https://doi.org/10.1371/journal.pone.0254184
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with few available targeted therapies. We previously reported that the phosphatase calcineurin (Cn) is required for LIC (leukemia Initiating Capacity) potential of T-ALL pointing to Cn as an interesting therapeutic target. Calcineurin inhibitors have however unwanted side effect. NFAT transcription factors play crucial roles downstream of calcineurin during thymocyte development, T cell differentiation, activation and anergy. Here we elucidate NFAT functional relevance in T-ALL. Using murine T-ALL models in which Nfat genes can be inactivated either singly or in combination, we show that NFATs are required for T-ALL LIC potential and essential to survival, proliferation and migration of T-ALL cells. We also demonstrate that Nfat genes are functionally redundant in T-ALL and identified a node of genes commonly deregulated upon Cn or NFAT inactivation, which may serve as future candidate targets for T-ALL.Keywords
Funding Information
- Ligue Contre le Cancer
- Fondation ARC pour la Recherche sur le Cancer
- University Paris Diderot
- University Paris Diderot
- University Paris Diderot
- Ligue Nationale Contre le Cancer
- Centre National de la Recherche Scientifique
- Institut National de la Santé et de la Recherche Médicale
This publication has 46 references indexed in Scilit:
- The genetics and molecular biology of T-ALLBlood, 2017
- Microenvironmental cues for T‐cell acute lymphoblastic leukemia developmentImmunological Reviews, 2016
- CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic LeukemiaCancer Cell, 2015
- CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia MaintenanceCancer Cell, 2015
- Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemiaLeukemia, 2013
- Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complexProceedings of the National Academy of Sciences of the United States of America, 2011
- NFAT, immunity and cancer: a transcription factor comes of ageNature Reviews Immunology, 2010
- Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras–initiated leukemiaJCI Insight, 2008
- Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemiaNature Medicine, 2007
- Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic LeukemiaScience, 2004