Epigenetic silencing of SOCS 5 potentiates JAK ‐ STAT signaling and progression of T‐cell acute lymphoblastic leukemia

Autor: Ksenia Matlawska-Wasowska, Wojciech Ornatowski, Huining Kang, Charles G. Mullighan, Roger B. Brown, Scott A. Ness, Mignon L. Loh, Stephen P. Hunger, Judy L. Cannon, Christian K. Nickl, Stuart S. Winter, Nitesh D. Sharma
Rok vydání: 2019
Předmět:
Zdroj: Cancer Science. 110:1931-1946
ISSN: 1349-7006
1347-9032
Popis: Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.
Databáze: OpenAIRE
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