Mariusz A. Wasik

faculty photo
Professor of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
University of Pennsylvania Medical Center
7.106 Founders and 413 Stellar Chance
3400 Spruce St/4283
Philadelphia, PA 19104
Office: (215) 662-3467
Fax: (215) 662-7529
Education:
M.D. (Medicine)
Wroclaw Medical Academy, Poland, 1979.
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Description of Research Expertise

Research Interests

Aberrant cell signaling and epigenetic regulation of gene expression in human lymphomas.

Research Summary

1. Role of the cytokine-signal transduction pathways and epigenetic gene silencing in pathogenesis of T-cell lymphoma.

Under this project my lab investigates the role of signals mediated through receptor for interleukin-2 (IL-2R) and functionally related cytokine receptors in malignant transformation of T lymphocytes. Part of the IL-2R, common chain ( c), is shared by receptors for several cytokines: IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. We found that cutaneous T-cell lymphoma cells display activation of the interleukin-2 receptor/cytokine common chain-associated Jak/STAT signal transduction pathway that is transient in the early stage of the lymphoma and constitutive in the late stage of the disease progression. More recently we determined that the constitutive Jak/STAT activation is due, at least in part, to the lack of expression of SHP-1 phosphatase, which normally down-regulates IL-2R/ c-mediated cell activating signals. Importantly, this work identified the mechanism underlying lack of SHP-1 expression as hypermethylation of the CpG DNA sequences within the SHP-1 promoter. This study may result in novel therapies for lymphoma based on selective inhibition of the elements of the IL-2R signal transduction pathway(s) which are preferentially utilized by malignant T cells and/or on induction of re-expression of the epigenetically-silenced SHP-1 gene. Our most recent work focuses on the molecular mechanisms of the aberrant gene silencing in the malignant lymphoid cells.

2. TOR signaling in posttransplant lymphoproliferative disorders (PTLDs) and other lymphoid malignancies.

Whereas the standard immunosuppressive agents foster development of PTLDs, the impact of novel immunosuppressive agents from the group of selective inhibitors of TOR serine/treonine kinase such as rapamycin and its derivatives including RAD remains undetermined. Our studies indicate that RAD has a strong inhibitory effect on PTLD-like and PTLD-derived B cells by suppressing their proliferation, blocking cell cycle progression and increasing apoptotic rate. In the in vivo SCID mouse xeno-transplant model, RAD markedly delayed growth or induced regression of established PTLD-related B-cell tumors. The drug completely eradicated or prevented tumor establishment in a subset of the treated mice at the doses matching the ones required to prevent graft rejection. These findings indicate that TOR inhibitors such as RAD may be effective in prevention and treatment of PTLDs and, possibly, other types of B-cell lymphoma. The molecular mechanism of this TOR inhibitor-mediated cell growth suppression is currently under investigation.

3. Mechanisms of malignant cell transformation by the chimeric NPM/ALK kinase.

Accumulating evidence indicates that expression of anaplastic lymphoma kinase (ALK) defines a distinct type of T-cell lymphoma. Expression of ALK in malignant T cells is typically due to the t(2;5) translocation resulting in formation of the fusion gene which encodes a 80-kDa hybrid protein that contains portion of the nuclear protein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK. The NPM/ALK kinase is constitutively activated and highly oncogenic. Our studies concentrate on identification of downstream effector molecules triggered by the NPM/ALK kinase. They indicate that pathways involving STAT3, PI3K/AKT and, apparently, STAT5 are constitutively activated by this kinase. Regulation and function of STAT3 in the ALK+ T-cells and testing an ALK-inhibitor small molecule candidate are the main focus of the ongoing investigation.

Description of Clinical Expertise

Hematopathology (tissue biopsy and blood smear interpretation) including related flow cytometry immunophenotyping and molecular pathology.

Selected Publications

M Kasprzycka, M Marzec, X Liu, Q Zhang, MA Wasik.: NPM/ALK oncoprotein induces expression of IL-10 and other features of the T regulatory cell phenotype by activating STAT3. Proc. Natl. Acad. Sci. USA 103: 9964-9969, 2006 Notes: (highlighted by a cover headline, ediors note and an invited commentary).

P Wlodarski, Q Zhang, X Liu, M Kasprzycka, M Marzec, MA Wasik.: PU.1 regulates transcription of SHP-1 in hematopoietic cells. J. Biol. Chem. 282: 6316-6323, 2007.

Q Zhang, HY Wang, X Liu, MA Wasik. : Stat5a is epigenetically silenced in the NPM/ALK-transformed T lymphocytes and acts in such cells as tumor suppressor by inhibiting expression of the NPM/ALK oncogene. Nature Med. 13(11): 1341-1348, 2007.

M Marzec, K Halasa, M Kasprzycka, JS Yoon, X Liu, J Tobias, D Baldwin, Q Zhang, N Odum, AH Rook, MA Wasik.: Differential effects of IL-2 and IL-15 vs. IL-21 on malignant CD4+ T lymphocytes. Cancer Res. 68: 1083-1091, 2008.

M Kasprzycka, Q Zhang, A Witkiewicz, M Marzec, M Potoczek, X Liu, HY Wang, M Milone, S Basu, J Mauger, JK Choi, JT Abrams, JS Hou, AH Rook, E Vonderheid, A Woetmann, N Odum, MA Wasik.: Gamma c-signaling cytokines induce a regulatory T cell phenotype in malignant CD4+ T lymphocytes. J. Immunol. 18: 2506-2512, 2008.

M Marzec, Q Zhang, A Goradia, PN Raghunath, X Liu, M Paessler, HY Wang, M Wysocka, M Cheng, B Ruggeri, MA Wasik: Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-LI, B7-H1). Proc. Natl. Acad. Sci. USA 105: 20852-20857, 2008.

Zhang Q, HY Wang, G Bhutani, X Liu, M Paessler, JW Tobias, D Baldwin, K Swaminathan, MC Milone, MA Wasik. : Lack of TNFa expression protects anaplastic lymphoma kinase-positive T-cell lymphoma (ALK+ TCL) cells from apoptosis. Proc. Natl. Acad. Sci. USA 106: 15843-15848, 2009

Vaites LP, Lee EK, Lian Z, Barbash O, Roy D, Wasik M, Klein-Szanto AJ, Rustgi AK, Diehl JA. : The Fbx4 tumor suppressor regulates Cyclin D1 accumulation and prevents neoplastic transformation. Mol. Cell. Biol. 31: 4513-4523, 2011.

M Marzec, X Liu, W Wong, Y Yang, T Pasha,K Kantekure, Q Zhang P, A Woetmann, M Cheng, N Odum, MA Wasik.: Oncogenic kinase NPM/ALK induces expression of HIF1a mRNA. Oncogene 30: 1372-1378. 2011.

Q Zhang, HY Wang, K Kantekure, JC Paterson, X Liu, A Schaffer, C Paulos, MC Milone, S Turner, G Inghirami, T Marafioti, MA Wasik: Oncogenic kinase NPM/ALK induces expression of the cell-growth stimulatory receptor ICOS. Blood 118 : 3062-3071, 2011.

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Last updated: 04/18/2014
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