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The circadian clock circuitry modulates leukemia initiating cell activity in T-cell acute lymphoblastic leukemia.
Murgo, Emanuele; De Santis, Elisabetta; Sansico, Francesca; Melocchi, Valentina; Colangelo, Tommaso; Padovano, Costanzo; Colucci, Mattia; Carbone, Annalucia; Totti, Beatrice; Basti, Alireza; Gottschlich, Lisa; Relogio, Angela; Capitanio, Nazzareno; Bianchi, Fabrizio; Mazzoccoli, Gianluigi; Giambra, Vincenzo.
Afiliación
  • Murgo E; Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS "Casa Sollievo Della Sofferenza", San Giovanni Rotondo, FG, 71013, Italy.
  • De Santis E; Hematopathology Unit, Fondazione IRCCS "Casa Sollievo Della Sofferenza", San Giovanni Rotondo, FG, 71013, Italy.
  • Sansico F; Hematopathology Unit, Fondazione IRCCS "Casa Sollievo Della Sofferenza", San Giovanni Rotondo, FG, 71013, Italy.
  • Melocchi V; Cancer Biomarkers Unit, Fondazione IRCCS "Casa Sollievo Della Sofferenza", San Giovanni Rotondo, FG, 71013, Italy.
  • Colangelo T; Cancer Biomarkers Unit, Fondazione IRCCS "Casa Sollievo Della Sofferenza", San Giovanni Rotondo, FG, 71013, Italy.
  • Padovano C; Hematopathology Unit, Fondazione IRCCS "Casa Sollievo Della Sofferenza", San Giovanni Rotondo, FG, 71013, Italy.
  • Colucci M; Hematopathology Unit, Fondazione IRCCS "Casa Sollievo Della Sofferenza", San Giovanni Rotondo, FG, 71013, Italy.
  • Carbone A; Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS "Casa Sollievo Della Sofferenza", San Giovanni Rotondo, FG, 71013, Italy.
  • Totti B; Hematopathology Unit, Fondazione IRCCS "Casa Sollievo Della Sofferenza", San Giovanni Rotondo, FG, 71013, Italy.
  • Basti A; Institute for Systems Medicine, Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, 20457, Germany.
  • Gottschlich L; Present Address: Ivana Türbachova Laboratory for Epigenetics, Epiontis, Precision for Medicine GmbH, Berlin, Germany.
  • Relogio A; Institute for Systems Medicine, Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, 20457, Germany.
  • Capitanio N; Institute for Systems Medicine, Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, 20457, Germany.
  • Bianchi F; Molekulares Krebsforschungszentrum (MKFZ), Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Mazzoccoli G; Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
  • Giambra V; Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
J Exp Clin Cancer Res ; 42(1): 218, 2023 Aug 24.
Article en En | MEDLINE | ID: mdl-37620852
ABSTRACT

BACKGROUND:

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, characterized by restricted cellular subsets with asymmetrically enriched leukemia initiating cell (LIC) activity. Nonetheless, it is still unclear which signaling programs promote LIC maintenance and progression.

METHODS:

Here, we evaluated the role of the biological clock in the regulation of the molecular mechanisms and signaling pathways impacting the cellular dynamics in T-ALL through an integrated experimental approach including gene expression profiling of shRNA-modified T-ALL cell lines and Chromatin Immunoprecipitation Sequencing (ChIP-Seq) of leukemic cells. Patient-derived xenograft (PDXs) cell subsets were also genetically manipulated in order to assess the LIC activity modulated by the loss of biological clock in human T-ALL.

RESULTS:

We report that the disruption of the circadian clock circuitry obtained through shRNA-mediated knockdown of CLOCK and BMAL1 genes negatively impacted the growth in vitro as well as the activity in vivo of LIC derived from PDXs after transplantation into immunodeficient recipient mice. Additionally, gene expression data integrated with ChIP-Seq profiles of leukemic cells revealed that the circadian clock directly promotes the expression of genes, such as IL20RB, crucially involved in JAK/STAT signaling, making the T-ALL cells more responsive to Interleukin 20 (IL20).

CONCLUSION:

Taken together, our data support the concept that the biological clock drives the expression of IL20R prompting JAK/STAT signaling and promoting LIC activity in T-ALL and suggest that the selective targeting of circadian components could be therapeutically relevant for the treatment of T-ALL patients.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Leucemia-Linfoma Linfoblástico de Células T Precursoras / Relojes Circadianos Límite: Animals / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2023 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Leucemia-Linfoma Linfoblástico de Células T Precursoras / Relojes Circadianos Límite: Animals / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2023 Tipo del documento: Article País de afiliación: Italia