Noncanonical β-catenin interactions promote leukemia-initiating activity in early T-cell acute lymphoblastic leukemia.

Autor:	Panelli P; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., De Santis E; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Colucci M; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Tamiro F; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Sansico F; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Miroballo M; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Murgo E; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Padovano C; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Gusscott S; Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC, Canada., Ciavarella M; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Chavez EA; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada., Bianchi F; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Rossi G; Department of Hematology and Stem Cell Transplant Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Carella AM; Department of Hematology and Stem Cell Transplant Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Steidl C; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada., Weng AP; Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC, Canada., Giambra V; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Mar 30; Vol. 141 (13), pp. 1597-1609.
DOI:	10.1182/blood.2022017079
Abstrakt:	T-cell acute lymphoblastic leukemia (T-ALL) is a T-cell malignancy characterized by cell subsets and enriched with leukemia-initiating cells (LICs). β-Catenin modulates LIC activity in T-ALL. However, its role in maintaining established leukemia stem cells remains largely unknown. To identify functionally relevant protein interactions of β-catenin in T-ALL, we performed coimmunoprecipitation followed by liquid chromatography-mass spectrometry. Here, we report that a noncanonical functional interaction of β-catenin with the Forkhead box O3 (FOXO3) transcription factor positively regulates LIC-related genes, including the cyclin-dependent kinase 4, which is a crucial modulator of cell cycle and tumor maintenance. We also confirm the relevance of these findings using stably integrated fluorescent reporters of β-catenin and FOXO3 activity in patient-derived xenografts, which identify minor subpopulations with enriched LIC activity. In addition, gene expression data at the single-cell level of leukemic cells of primary patients at the time of diagnosis and minimal residual disease (MRD) up to 30 days after the standard treatments reveal that the expression of β-catenin- and FOXO3-dependent genes is present in the CD82+CD117+ cell fraction, which is substantially enriched with LICs in MRD as well as in early T-cell precursor ALL. These findings highlight key functional roles for β-catenin and FOXO3 and suggest novel therapeutic strategies to eradicate aggressive cell subsets in T-ALL. (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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