Epigenetic silencing of SOCS5 potentiates JAK‐STAT signaling and progression of T‐cell acute lymphoblastic leukemia

Abstract

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 .

Leonurine-Repressed miR-18a-5p/SOCS5/JAK2/STAT3 Axis Activity Disrupts CML malignancy

“…A lot of evidences suggest that SOCS5 serves as a tumor suppressor in cancers by negatively regulating JAK2/STAT3 (Zhang Z. et al, 2019;Yang et al, 2020). Although SOCS5 dysregulation has been recently associated with acute and chronic lymphocytic leukemia (Toniolo et al, 2016;Sharma et al, 2019), its role in CML has not been characterized to date. In the FIGURE 6 | Leonurine suppresses CML xenograft growth in vivo (A) The expression of miR-18a-5p in K562 cells stably infected with lentivirus harboring miR-18a-5p inhibitor (LV-miR-inhibitor) or negative control (Lv-miR-NC) (B) Cells were injected subcutaneously into nude mice.…”

“…JAK2/STAT3 signaling is negatively regulated by many regulators, including the suppressor of cytokine signaling (SOCS) family (Johnson et al, 2018). A recent study suggests that SOCS5 downregulation potentiates aberrant JAK2-STAT3 signal transduction to promote T-cell acute lymphoblastic leukemia (T-ALL) progression (Sharma et al, 2019). However, little is known about the mechanism by which SOCS5 regulates signal transduction in CML.…”

The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

“…SOCS5 serves as a tumor suppressor gene in several types of malignancies via its negative regulatory effects on the epidermal growth factor (EGF) receptor and JAK-STAT signaling pathways [114,115]. Our group reported downregulation of SOCS5 mRNA and protein levels in high-risk T-ALL with KMT2A rearrangements [72]. In fact, gene expression analyses identified SOCS5 within the most downregulated genes in high-risk T-ALL samples harboring KMT2A rearrangements [116].…”

“…Mechanistically, SOCS5 depletion induced the activation of JAK-STAT signaling and downregulation of both IL-4 and IL-7 receptors. In addition to T-ALL, downregulation of SOCS5 mRNA was found in B-ALL and AML primary samples harboring chromosomal alterations involving the KMT2A gene [72]. Moreover, forced expression of KMT2A-MLLT4 and KMT2A-MLLT1 in Ba/F3 cells reduced SOCS5 protein levels and enhanced JAK-STAT signaling activation [72].…”

Deregulation of the Interleukin-7 Signaling Pathway in Lymphoid Malignancies

“…Furthermore, the arginine to serine substitution at residue 98 (R98S) of RPL10, a mutation identified in up to 8% of patients with T-ALL, was shown to increase the expression of IL7R and downstream signaling molecules [ 60 ]. Lastly, the reduced expression of SOCS5 was found in T-ALL patients with KMT2A translocations and resulted in the upregulation of IL-7Rα expression levels and the activation of JAK-STAT signaling, thereby promoting T-ALL cell proliferation in vitro and in vivo [ 61 ].…”