Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T‐cell leukemia/lymphoma

Abstract

Adult T‐cell leukemia/lymphoma (ATLL) is a mature T‐cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK‐STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression‐free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.

Genome-wide CRISPR screens identify CD48 defining susceptibility to NK cytotoxicity in peripheral T-cell lymphomas

“…Primary ATLL cells expressed surface CD48 protein in approximately 50% reduction ( Figure 6 C), which might be sufficient to confer a survival advantage, particularly when accumulated over the years. We found that disruption of the IL2/STAT5B axis decreased CD48 expression in IL2-dependent ATLL cell lines, mirroring the fact that primary ATLL cells rarely showed activated STAT5 24 and appeared unresponsive to IL-2 in a majority of ATLL cases, especially in the aggressive phase. 25 , 26 Lymphoma cells in other aggressive PTCL subtypes also showed decreased concentrations of CD48 expression.…”

From drug repositioning to target repositioning: prediction of therapeutic targets using genetically perturbed transcriptomic signatures

“…Protein–protein interaction network analysis using the STRING database ( Snel et al , 2000 ) identified the SRC node as having the highest degree. SRC is a proto-oncogene that interacts with STAT3, one of the causal genes of ATL ( Garcia et al , 2001 ; Morichika et al , 2019 ). SRC is also the target of the drug dasatinib, and its ingredients have been reported to have therapeutic effects on ATL ( Kodama et al , 2019 ).…”

The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma

“…Some studies have evaluated both staining intensity and percentage of positive cells for pSTAT3 expression, 14,47 however, most of these studies have simply analyzed the positive rate of expression. 10,15,48,49 Although unphosphorylated STAT3 can be functional by modulating gene expression of IL-6 or IL-10, 50,51 most previous studies used the nuclear expression of pSTAT3 as a surrogate marker of STAT3 activation. Furthermore, a recent study using reverse-phase protein arrays identified that pSTAT3 and total STAT3 expression largely correlated in anaplastic large cell lymphoma.…”