Phospho-STAT3 Is Active in the Majority of Anaplastic Large Cell Lymphomas with ALK Translocation
Robin Rawson, Randa Alsabeh, Serhan Alkan. Cedars-Sinai Medical Center, Los Angeles, CA
Background: Anaplastic large cell lymphoma (ALCL) is a non-Hodgkin lymphoma with many cases showing chromosomal translocation of the Anaplastic Lymphoma Kinase (ALK) gene with the nucleophosmin gene (ALK-NPM); t(2;5). ALK proteins have homo-dimerization domains resulting in constitutive activation and phosphorylation of the ALK tyrosine kinase. Established cell lines have shown that the ALK protein leads to constitutive activation of Jak3 and phosphorylation of STAT3 (pSTAT3) leading to protection from cell death. Gene-expression studies in peripheral T-cell lymphoma suggest a correlation of ALK activation with STAT3 expression. However, studies integrating pSTAT3 status in ALCL in patient materials are limited. Therefore, we have examined pSTAT3 expression in ALK positive and negative cases of ALCL with T-cell lineage.
Design: In order to characterize the expression of phosphorylated STAT3 in ALCL, 18 cases of previously diagnosed ALCL were identified. STAT3 staining with an antibody recognizing the STAT3 phosphorylated tyrosine (705) was performed on paraffin embedded tissue and graded according to percent positive staining of lymphoma cells. A cut-off of 20% positivity of lymphoma cells was used to classify a case as positive. A case of Hodgkin disease with Reed-Sternberg cells were used as positive controls with prominent staining of pSTAT3 in the Reed-Sternberg cells, consistent with previous reports of positivity with pSTAT3. Endothelial cells were used as an internal control which frequently showed positivity.
Results: Out of 18 cases of ALCL, six cases of ALCL were found to show positivity for nuclear expression of ALK while twelve cases were negative. All six of the cases of ALK positive ALCL showed positivity for pSTAT3 varying from 1+ to 4+ positivity (greater than 20-90% of lymphoma cells staining). Seven of twelve cases of ALK negative ALCL showed positive staining for pSTAT3 with positivity varying from 1-4+ (30-100% of lymphoma cells). One of the ALK negative ALCL cases included was associated with breast implant and showed strong expression of pSTAT3.
Conclusions: Phosphorylated STAT3 is positive in all cases of ALK positive ALCL and many ALK negative ALCL. The ALK negative ALCL with expression of pSTAT3 is likely activated by an alternative pathway. Considering the recent evolution of tyrosine kinase inhibitors against the JAK/STAT pathway including STAT3, ALCL cases with activated STAT3 may be considered for alternative treatment in patient's with resistant disease. Therefore, future clinical trials targeting this pathway are warranted.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 189, Wednesday Morning