Open AccessEpigenetic silencing of SOCS 5 potentiates JAK ‐ STAT signaling and progression of T‐cell acute lymphoblastic leukemia
Author(s) -
Sharma Nitesh D.,
Nickl Christian K.,
Kang Huining,
Ornatowski Wojciech,
Brown Roger,
Ness Scott A.,
Loh Mig L.,
Mullighan Charles G.,
Winter Stuart S.,
Hunger Stephen P.,
Can Judy L.,
MatlawskaWasowska Ksenia
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14021
Subject(s) - socs3 , cancer research , gene silencing , biology , signal transduction , suppressor of cytokine signaling 1 , cytokine , dna methylation , socs5 , socs6 , cell growth , microbiology and biotechnology , immunology , stat3 , gene expression , suppressor , cancer , genetics , gene
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 ( SOCS 5) in T‐ ALL cellular signaling networks and leukemia progression. We found that SOCS 5 was differentially expressed in primary T‐ ALL and its expression levels were lowered in HOXA ‐deregulated leukemia harboring KMT 2A gene rearrangements. Here, we report that SOCS 5 expression is epigenetically regulated by DNA methyltransferase‐3A‐mediated DNA methylation and methyl CpG binding protein‐2‐mediated histone deacetylation. We show that SOCS 5 negatively regulates T‐ ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS 5 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 SOCS 5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS 5 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 SOCS 5 expression to the enhanced activation of the JAK ‐ STAT and cytokine receptor‐signaling cascade in T‐ ALL .