STAT signaling in the pathogenesis and treatment of leukemias

Lin, Thomas S.; Mahajan, Sudipta; Frank, David A.

doi:10.1038/sj.onc.1203486

Cited by 227 publications

(187 citation statements)

References 45 publications

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“…Constitutive activation of STAT3 has been observed in breast cancer, prostate cancer and leukaemia (Schuringa et al, 2000;Lin et al, 2000b;Campbell et al, 2001;Li and Shaw, 2002). Recent studies also found that blockade of STAT3 activity by the expression of the dominant-negative STAT3 can inhibit growth of AGS gastric cancer cell line, thus further suggesting that JAK/STAT may play an important role in development of gastric cancer (Kanai et al, 2003).…”

Section: Discussionmentioning

confidence: 96%

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

Chan

Leung

et al. 2004

Br J Cancer

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The interleukin-mediated Janus kinase (JAK)/STAT pathway plays a crucial role in carcinogenesis. Recently, increased STAT3 activity was found in hepatocellular carcinoma and multiple myeloma in which there was silencing of SOCS-1 (suppressor of cytokine signalling-1) by gene promoter hypermethylation. We investigated the expression level of interleukin-6 (IL-6) and SOCS-1 in gastric cancer cell lines. Expression of SOCS-1 correlated with IL-6 level in most of the cell lines, except for AGS cells in which SOCS-1 was absent despite a high level of IL-6 production. Methylation analysis by methylation-specific polymerase chain reaction and bisulphite sequencing revealed that CpG island of SOCS-1 was densely methylated in AGS cells. Demethylation treatment by 5 0 azadeoxycytidine restored SOCS-1 expression and also suppressed constitutive STAT3 phosphorylation in AGS cells. Moreover, methylation of SOCS-1 was detected in 27.5% (11 of 40) of primary gastric tumours samples, 10% (one of 10) of adjacent noncancer tissues but not in any (zero of nine) normal gastric mucosa. Methylation of SOCS-1 also correlated with the loss of mRNA expression in some primary gastric cancers. In conclusion, this is the first report to demonstrate that hypermethylation of SOCS-1 led to gene silencing in gastric cancer cell line and primary tumour samples. Downregulation of SOCS-1 cooperates with IL-6 in the activation of JAK/STAT pathway in gastric cancer.

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Section: Discussionmentioning

confidence: 96%

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

Chan

Leung

et al. 2004

Br J Cancer

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“…It has been found aberrantly activated in leukemia and lymphoma as well as solid cancers as breast and prostate cancer (reviewed in refs. [43][44][45]. In this light, it is surprising how little is known about the function of STAT5 and its downstream targets in CTCL.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…Upon activation by tyrosine phosphorylation, STATs enter the nucleus and modulate expression of genes involved in many functions, including survival, differentiation and apoptosis (Horvath, 2000). Aberrant activation of STATs, especially STAT5, is found in numerous cancers, including hematopoietic cancers (Frank, 1999;Bowman et al, 2000;Lin et al, 2000). Chronic myelogenous leukemia (CML) is a prototypical tumor displaying constitutive STAT5 activation.…”

Section: Introductionmentioning

confidence: 99%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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Deregulated expression of BCL6 is a pathogenic event in many lymphomas. BCL6 blocks cellular differentiation by repressing transcription of its target genes, and this may promote tumorigenesis. Conversely, the transcription factor signal transducers and activators of transcription (STAT)5 promotes differentiation in many systems. STAT5 upregulates a number of genes repressed by BCL6, raising the possibility that STAT5 and BCL6 have opposing roles in transcriptional regulation. Therefore, we sought to determine the effects of STAT5 activation on BCL6 expression and function. We found that activation of STAT5 downregulates BCL6 expression in B-lymphoma cells and other hematopoietic cell lines. We identified two potential STAT-binding regions in the first exon and first intron of BCL6 that fell within regions of high interspecies homology, suggesting conservation of regulatory function. STAT5 can bind inducibly and regulate transcription at one of these regions, identifying BCL6 as a STAT5 target gene. Additionally, STAT5-mediated downregulation of BCL6 results in loss of BCL6 repression of its target genes, confirming that STAT5 is a negative regulator of BCL6 function. The STAT5 responsive region of the BCL6 gene is mutated frequently in B-cell lymphomas, suggesting that loss of the repressive effects of STAT5 on BCL6 might contribute to the pathogenesis of these cancers.

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STAT signaling in the pathogenesis and treatment of leukemias

Cited by 227 publications

References 45 publications

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

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

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

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