Description of Research Expertise:
Aberrant cell signaling and epigenetic regulation of gene expression in human lymphomas.
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.
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: Chimeric antigen receptor modified T cells directed against CD19 (CTL019) induce clinical responses in patients with relapsed or refractory CD19+ lymphomas. Cytotherapy 17 (6): S13,2015.
Li Y, Chitnis N, Nakagawa H, Kita Y, Natsugoe S, Yang Y, Li Z, Wasik M, Klein-Szanto AJ, Rustgi AK: PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov. 5 (3): 288-303,2015.
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: IL-15 and IL-17F are differentially regulated and expressed in mycosis fungoides (MF). Cell Cycle 13 (8): 1306-1312,2014.
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: STAT3 Activation and Infiltration of Eosinophil Granulocytes in Mycosis Fungoides. Anticancer Res. 34 (10): 5277-5286,2014.
Krejsgaard T, Willerslev-Olsen A, Lindahl LM, Bonefeld CM, Koralov SB, Geisler C, Wasik MA, Gniadecki R, Kilian M, Iversen L, Woetmann A: Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation. Blood 124 (5): 761-770,2014.
Hameed UF, Lim J, Zhang Q, Wasik MA, Yang D: Transcriptional repressor domain of MBD1 is intrinsically disordered and interacts with its binding partners in a selective manner. Sci Rep. 4 : 4896,2014.
Luskin MR, Roy DB, Wasik MA: Development of lymphomas containing Epstein-Barr virus following therapy with hyper-CVAD regimen. Clin Lymphoma Myeloma Leuk. 14 (2): e55-58,2014.
Moti N, Malcolm T, Hamoudi R, Mian S, Garland G, Hook CE, Burke GA, Wasik MA, Merkel O, Kenner L, Laurenti E, Dick JE: Anaplastic large cell lymphoma-propagating cells are detectable by side population analysis and possess an expression profile reflective of a primitive origin.
Oncogene 34 (14): 1843-1852,2015.
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: Cutaneous T cell lymphoma expresses immunosuppressive CD80 (B7-1) cell surface protein in a STAT5-dependent manner. J Immunol. 192 (6): 2913-2919,2014.
Stonecypher M, Yan Z, Wasik MA: Intravascular Large B-cell Lymphoma presenting as a thyroid mass. Endocrine Pathol. 25 (3): 359-360,2014.
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: MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T cell lymphoma. Anticancer Res. 34 (12): 7207-7217,2014.
Marzec M, Halasa K, Liu X, Wang HY, Cheng M, Baldwin D, Tobias JW, Schuster SJ, Woetmann A, Zhang Q, Turner SD, Odum N: Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming. J Immunol. 191 (12): 6200-6207,2013.
Wasik MA, Jimenez GS: Targeting CD30 in malignant tissues: challenges in detection and clinical applications. Pathobiology 80 (5): 252-258,2013.
Yao S, Cheng M, Zhang Q, Wasik M, Kelsh R: Anaplastic lymphoma kinase is required for neurogenesis in the developing zebrafish central nervous system of zebrafish. PLoS One 8 (5): e63757,2013.
Lee SC, Marzec M, Liu X, Wehrli S, Kantekure K, Ragunath PN, Nelson DS, Delikatny EJ, Glickson JD: Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma. NMR Biomed. 26 (1): 106-114,2013.
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