PEOPLE

Mariusz A. Wasik, MD

Professor of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania
University of Pennsylvania Perelman School of Medicine

Contact InformationDepartment of Pathology and Laboratory Medicine
280 John Morgan Building
3620 Hamilton Walk
Philadelphia, PA 19104
Office: (215) 662-3467
Fax: (215) 662-7529

Email: WASIK@MAIL.MED.UPENN.EDU

Specialty Division

Hematopathology, Immunobiology and Experimental Pathology

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.

Clinical Expertise

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

Itmat Expertise

Dr. Wasik is interested in cell signal transduction (Jak/STAT, mTOR, P13K/Akt), small molecule-mediated kinase inhibition, epigenetic silencing of expression of tumor suppressor genes and pathogenesis and diagnosis of lymphomas.

Graduate Groups

Cell and Molecular Biology
Immunology

Education

M.D. (Medicine), Wroclaw Medical University, Poland, 1979

Specialty Certification

Diplomate in Anatomic Pathology, American Board of Pathology, 1991
Diplomate in Hematology, American Board of Pathology, 1993

Postgraduate Training

Transitional year (internal medicine, surgery, pediatrics, obstetrics and gynecology), Wroclaw Medical Academy, Wroclaw, Poland, 1979-1980
Fellow, Department of Pathology, Harvard Medical School, Boston, MA and Laboratory of Immunology, Evans Department of Clinical Research , Boston University Medical Center, Boston, MA, 1985-1987
Fellow, Division of Tumor Immunology, Dana-Farber Cancer Institute and Department, Pathology, Harvard Medical School, Boston, MA, 1987-1988
Resident and Chief Resident in Anatomic Pathology Resident and Chief Resident in Anatomic Pathology , Mallory Institute of Pathology, Boston, MA, 1988-1991
Fellow in Hematopathology, Department of Pathology, Beth Israel Hospital and Harvard Medical School, Boston, MA, 1991-1993

Awards and Honors

Magna cum Laude graduate, 1979
National Cancer Institute Shannon Award, 1999
Member of the National Institute of Health Study Section on Tumor Cell Biology (ad hoc: October 2003, October 2006, February 2007, and June 2007 sessions; chartered membership from July 2007 to June 2011), 2003-2011
Review of NCI SPORE appl.: Oct 2003, Sept 2006, June 2008, Feb 2009, July 2009; meeting chair, Feb 2012; chair, May 2012; chair, Sept 2012; chair, June 2013; chair, Feb 2014; chair, Oct 2014, Sept 2015, Feb 2016, June 2016; chair, Feb 2017, June 2017., 2003-present
Member of the National Institute of Health Cancer Research Fellowship Study Section (July and Nov 2004 and Nov 2005), 2004-2005
Member of the National Institute of Health Program Project Review Committees: Feb 2004, Sept 2004, Jan 2005, March 2005, Feb 2007, Feb 2008, May 2010, June 2011, June 2012; meeting chair, Sept 2016., 2004-present
Member of the National Cancer Institute Rapid Access to Intervention Development (RAID) Review Committee (Nov 2005), 2005
Member of the Ariad Co. Advisory Board on mTOR inhibitor, 2005
Member of the Scientific Advisory Board, Cephalon Inc., Oncology Program, 2005-2011
Grant application reviewer for The Netherlands Organization for Health Research and Development, 2006
Grant application reviewer for Cancer Research United Kingdom, 2007
Grant application reviewer for The Vienna Science and Technology Fund, 2007
Expert for the NCI/CTEP IDSC Signal Transduction Task Force, 2008
Grant application reviewer for the Austrian Science Fund, 2008
Member of the Lymphoma Research Foundation’s Panel of Scientific Consultants (sessions 2008, 2011, 2012, 2013), 2008-present
Grant application reviewer for the NIH Pathway to Independence program, 2009
Grant application reviewer for the Neuroblastoma Society, United Kingdom, 2010
North American CD30 Pathology Advisory Board (Oct. 2011, Nov 2013)., 2011
Member of the National Institute of Health Special Emphasis and Provocative Questions grant reviews: Dec 2012; meeting chair, May 2013, Oct 2013, June 2015, Apr 2016, Nov 2016, 2012-present

Memberships and Professional Organizations

University of Pennsylvania Graduate Group in Cell and Molecular Biology, 2101 - present
Academy of Clinical Laboratory Physicians and Scientists (1996- ), - Present
Society for Hematopathology (2000- ), - Present
University of Pennsylvania Institute for Translational Medicine and Therapeutics (2005- present), - Present
University of Pennsylvania Graduate Group in Immunology (1997- ), - Present
American Association for Advancement of Science (1987-88 and 1993-present)
American Society for Investigative
Pathology (1994- ), International Society for Cutaneous Lymphomas (1995- ), - Present
University of Pennsylvania Cancer Center (1995- ), - Present

Selected Publications

Chimeric antigen receptor modified T cells directed against CD19 (CTL019) induce clinical responses in patients with relapsed or refractory CD19+ lymphomas.

Levine BL, Svoboda J, Nasta SD, Porter D, Chong EA, Lacey SF, Mahnke YD, Melenhorst JJ, Chew A, Shah GD, Hasskar J, Wasik MA, Landsburg DJ, Mato A, Garfall AL, Frey NV, Shaw PA, Marcucci KT, Shea J, McConville H, Manvar N, O'Rourke DM, Lamontagne A, Bersenev A, Zheng Z, Schuster SJ, June CH, Cytotherapy 17(6): S13, 2015

PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers.

Li Y, Chitnis N, Nakagawa H, Kita Y, Natsugoe S, Yang Y, Li Z, Wasik M, Klein-Szanto AJ, Rustgi AK, Diehl JA, Cancer Discov. 5(3): 288-303, 2015, PMID:25582697

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IL-15 and IL-17F are differentially regulated and expressed in mycosis fungoides (MF).

Willerslev-Olsen A, Litvinov IV, Fredholm SM, Petersen DL, Sibbesen NA, Gniadecki R, Zhang Q, Bonefeld CM, Wasik MA, Geisler C, Zhou Y, Woetmann A, Sasseville D, Krejsgaard T, Odum N, Cell Cycle 13(8): 1306-1312, 2014, PMID:24621498

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STAT3 Activation and Infiltration of Eosinophil Granulocytes in Mycosis Fungoides.

Fredholm S, Gjerdrum LM, Willerslev-Olsen A, Petersen DL, Nielsen IO, Kauczok CS, Wobser M, Ralfkiaer U, Bonefeld CM, Wasik MA, Krejsgaard T, Geisler C, Ralfkiaer E, Gniadecki R, Woetmann A, Odum N, Anticancer Res. 34(10): 5277-5286, 2014, PMID:25275020

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Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation.

Krejsgaard T, Willerslev-Olsen A, Lindahl LM, Bonefeld CM, Koralov SB, Geisler C, Wasik MA, Gniadecki R, Kilian M, Iversen L, Woetmann A, Odum N, Blood 124(5): 761-770, 2014, PMID:24957145

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Transcriptional repressor domain of MBD1 is intrinsically disordered and interacts with its binding partners in a selective manner.

Hameed UF, Lim J, Zhang Q, Wasik MA, Yang D, Swaminathan K, Sci Rep. 4(): 4896, 2014, PMID:24810720

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Development of lymphomas containing Epstein-Barr virus following therapy with hyper-CVAD regimen.

Luskin MR, Roy DB, Wasik MA, Loren AW, Clin Lymphoma Myeloma Leuk. 14(2): e55-58, 2014, PMID:24393621

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Anaplastic large cell lymphoma-propagating cells are detectable by side population analysis and possess an expression profile reflective of a primitive origin.

Moti N, Malcolm T, Hamoudi R, Mian S, Garland G, Hook CE, Burke GA, Wasik MA, Merkel O, Kenner L, Laurenti E, Dick JE, Turner SD, Oncogene 34(14): 1843-1852, 2015, PMID:24814516

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Intravascular Large B-cell Lymphoma presenting as a thyroid mass.

Stonecypher M, Yan Z, Wasik MA, LiVolsi V, Endocrine Pathol. 25(3): 359-360, 2014, PMID:24014041

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Cutaneous T cell lymphoma expresses immunosuppressive CD80 (B7-1) cell surface protein in a STAT5-dependent manner.

Zhang Q, Wang HY, Wei F, Liu X, Paterson JC, Roy D, Mihova D, Woetmann A, Ptasznik A, Odum N, Schuster SJ, Marafioti T, Riley JL, Wasik MA, J Immunol. 192(6): 2913-2919, 2014, PMID:24523507

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Targeting CD30 in malignant tissues: challenges in detection and clinical applications.

Wasik MA, Jimenez GS, Weisenburger DD, Pathobiology 80(5): 252-258, 2013, PMID:23689361

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Anaplastic lymphoma kinase is required for neurogenesis in the developing zebrafish central nervous system of zebrafish.

Yao S, Cheng M, Zhang Q, Wasik M, Kelsh R, Winkler C, PLoS One 8(5): e63757, 2013, PMID:23667670

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Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming.

Marzec M, Halasa K, Liu X, Wang HY, Cheng M, Baldwin D, Tobias JW, Schuster SJ, Woetmann A, Zhang Q, Turner SD, Odum N, Wasik MA, J Immunol. 191(12): 6200-6207, 2013, PMID:24218456

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MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T cell lymphoma.

Ralfkiaer U, Lindahl LM, Litman T, Gjerdrum LM, Ahler CB, Gniadecki R, Marstrand T, Fredholm S, Iversen L, Wasik MA, Bonefeld CM, Geisler C, Krejsgaard T, Glue C, Ropke MA, Woetmann A, Skov L, Gronaek K, Odum N, Anticancer Res. 34(12): 7207-7217, 2014, PMID:25503151

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Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma.

Lee SC, Marzec M, Liu X, Wehrli S, Kantekure K, Ragunath PN, Nelson DS, Delikatny EJ, Glickson JD, Wasik MA, NMR Biomed. 26(1): 106-114, 2013, PMID:22711601

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