IL-2R common γ-chain is epigenetically silenced by nucleophosphin–anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK

Abstract

Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4 + T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4 + T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of the IL-2Rγ gene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to the IL-2Rγ gene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

“…STAT3 was recently shown to regulate miR-21 expression in malignant T cells. 33,34 As siRNA directed against STAT3 resulted in an almost complete depletion of STAT3 without modulating the expression of BIC and miR-155 ( Fig. 3A and B), it appears that STAT3 and STAT5 have distinct and specialized roles regulating miR-21 and miR-155, respectively.…”

“…Interestingly, miR-21, another oncogenic miRNA that is significantly upregulated in CTCL patients, 17,18 was shown to be modulated by STAT3. 33,34 Much less is known about STAT5, another downstream effector of the IL-2R/JAK3 complex. A previous study indicated that STAT5 is aberrantly activated in CTCL, but only a small number of patients was analyzed, and the pathological relevance was unclear.…”

Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation

“…However, the role of STAT3 acetylation in human cancer has not been determined. Although STAT3 is a well-known transcriptional activator for many genes (3,4), recently it has also been reported to inhibit gene expression (5)(6)(7)(8)(9). Although the underlying mechanisms remain to be further explored, STAT3 has been shown to increase CpG island methylation of certain tumor-suppressor genes through regulating expression and interacting with DNA methyltransferase 1 (DNMT1) (5)(6)(7).…”

“…Although STAT3 is a well-known transcriptional activator for many genes (3,4), recently it has also been reported to inhibit gene expression (5)(6)(7)(8)(9). Although the underlying mechanisms remain to be further explored, STAT3 has been shown to increase CpG island methylation of certain tumor-suppressor genes through regulating expression and interacting with DNA methyltransferase 1 (DNMT1) (5)(6)(7). DNMT1 is primarily involved in the maintenance of methylation (10)(11)(12), but it also is required for aberrant CpG methylation in human cancer cells (13,14).…”

The pathobiology of the oncogenic tyrosine kinase NPM-ALK: a brief update

“…One example is the observation that STAT3 functionally interacts with DNA methyltransferases, and thereby promotes promoter hypermethylation and gene silencing [Zhang et al , 2011b. One gene is SHP1, which encodes a tyrosine phosphatase that negatively regulates the STAT3 signaling pathway Han et al 2006aHan et al , 2006bHonorat et al 2006].…”