Possible New Target for Novel Targeting Therapies in the Treatment of Patients with ALK-ALCL

ggi9001By Giorgio Inghirami, MD

Although the role of ALK chimeras is well known in the pathogenesis of ALK + Anaplastic Large Cell Lymphoma (ALCL), the mechanisms underlying the transformation of ALK-ALCL is unknown. In an abstract presented before the 56th Annual Meeting of the American Society of Hematology we provided a comprehensive characterization of the various driving genetic alterations that led to the constitutive activation of STAT3 in ALK-ALCL.

This characterization was reached by combining Whole Exome Sequencing (WES), Copy Number Variation analysis and RNAseq in a discovery panel (5 ALK+ and 18 ALK- ALCL). The frequency of JAK/STAT3 mutations was further tested by Sanger and deep sequencing analyses, in an independent panel of 158 ALCL (88 ALK-, 26 ALK+ ALCL and 44cALCL) AND 67 PTCL. Functional tests were completed by transfection/transduction of different cells lines (STAT3 -/- MEF, HEK-293T, SUPM2 TTA and SUPM2 S3S), in association with Western Blot, and using cells viability analyses, Luciferase Assay, 2D and soft agar colony assays.

From the gathered data we were able to demonstrate that a subset of ALK-ALCL displays the constitutive activation of JAK/STAT3 pathway via multiple mechanisms. These mechanisms could be significantly abrogated by specific inhibitors like JAK1/2 and ROS1. With the central role of STAT3 there is the possibility of using novel targeting strategies to provide new avenues for the treatment of ALK- ALCL patients as suggested in our preclinical ALC PDT model.

Author: lymphomaprogram

Located on the Upper East Side of New York City, the Lymphoma Program at Weill Cornell Medical College/NewYork Presbyterian Hospital is internationally recognized for our efforts to enable patients with non-Hodgkin lymphoma, Hodgkin disease and related disorders to have the best possible clinical outcome, including cure when possible.

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