Dr. Gupta is an Assistant Professor of Biochemistry and Molecular Medicine, the George Washington University School of Medicine & Health Sciences. Dr. Gupta’s areas of expertise are cancer biology, epigenetics and tumor microenvironment (TME). During her career, Dr. Gupta has worked extensively on several aspects of these areas including molecular/oncogenic signaling, epigenetic regulation such as histone deacetylases, chromatin modifying enzymes, long non-coding RNAs and role of cytokines in TME. Overall, her current research areas are focused on the (1) molecular and cellular aspects of long non-coding RNAs in tumor and tumor microenvironment using lymphoma as disease model. (2) Role of JAK/STAT signaling and mechanisms of resistance to targeted therapies in T-cell lymphoma. (3) Role of RNA methyltransferase METTL3 and epigenetic reader protein BRD4 in melanoma.
Research
Regulation of JAK2 kinase in lymphoma
The Janus kinase 2 (JAK2)/signal transducers and activators of transcription (STAT) pathway play an important role in the pathogenesis of hematological malignancies. We have demonstrated that signaling through JAK2 and STAT3 is found active in more than 50% of lymphoma patients; and that inhibition of pathway by JAK2 inhibitor, TG101348 (TG) induces growth inhibition and apoptosis in a variety of lymphoma cell lines and patient samples. Studying 3 different scenarios of JAK/STAT signaling in NHL we have identified: 1) Genetic variations in JAK2 and STAT3 genes that led to identification of novel point mutations in JAK2 and STAT3 in DLBCL. 2) negative regulators of the STAT pathway - Suppressors of cytokine signaling (SOCS1) and protein tyrosine phosphatases (SHP1) found suppressed in 33% and 86% of DLBCL samples, respectively; and we have defined epigenetic mechanisms of silencing of PTPN6 (SHP1) in NHL and, 3) JAK/STAT pathway-specific cytokines (IL-2, IL-6, IL-10 and EGF) in serum samples from patients with DLBCL and revealed that enhanced serum levels of IL-10 contributes towards JAK2 activation; and that JAK2 inhibition with inhibitor, TG101348 inhibits autocrine production of IL-10 in DLBCL cells. These preclinical data provide the rationale to test JAK2 inhibitors in relapsed lymphoma cases. Since these agents have been already tested in clinical trials for myeloproliferative neoplasms, issues of their safety and clinical activity are partially addressed. We have proposed a trial design that will test the hypothesis that patient pre-selection based on tumor cell STAT3 activation status will improve the clinical outcome.
Epigenetic modulation through HDACs and long non-coding RNAs
Epigenetic processes control normal embryonic development and growth; however, deregulated epigenetic processes also found in diseases such as cancer. As components of several multi-protein complexes, Class I HDACs such as HDAC1-3 are ubiquitously expressed nuclear enzymes regulating numerous cellular processes. Genetic ablation studies have shown that class I HDACs are involved in cell proliferation and survival; moreover, recently we have shown that HDAC3 can physically associate with STAT3 and directly regulates STAT3 activation in the diffuse large B cells. We have also reported that histone deacetylase inhibitors (HDACi), such as panobinostat (LBH589) by blocking Akt activity can synergize antitumor activity of mTOR inhibitors. The epigenome can mark DNA in two ways, both of which play a role in turning genes off or on. We have recently uncovered that lack of SHP1 a tumor suppressor gene found silenced in majority of DLBCL patients is associated with DNA hypermethylation at CpG2 sites in the promoter region of the gene. I have also discovered novel lncRNAs ROR1-AS1 overexpressed in mantle cell lymphoma and play an epigenetic role through PRC2 and EZH2. Moreover we have also shown role of GAS5 lncRNA in the MYC translation.
Grants
- Grant: P50 CA97274-12 (National Cancer Institute/NIH).
Lymphoma SPORE
Date: 07/01/2012-06/30/2017
Goal: Targeting JAK kinase in non-Hodgkin lymphoma.
Role: Co-project leader for-Project 3 - ASH Bridge Grant (American Society of Hematology)
Date: 2015-2017
Goal: Role of translation inititation factor-4E in aggressive lymphoma
Role: PI
- 2002: Fellowship Award, Union for International Cancer Control (UICC).
- 2009: Developmental Research Award, University of Iowa/Mayo Clinic Lymphoma SPORE.
- 2010-12: Career Development Award, University of Iowa/Mayo Clinic Lymphoma SPORE.
- 2012: Clinomics Translational Research Award, Center for Individualized Medicine(CIM), Mayo Clinic.
- 2015-17: ASH Bridge Award from American Society of Hematology
Teaching
Dr. Gupta has been actively involved in the master's program and graduate school courses at the GWU.
- BIOC 6221
Proteins, Pathways and Human Health - BIOC 6222
Biochemical Genetics and Medicine - CANC 8221
Introduction to Basic Oncology - CANC 8222
Molecular Oncology and Cancer Epigenetics
Center and Institutes
- GW Cancer Center (GWCC)
(* Corresponding author)
1. RNA m6A methyltransferase METTL3 regulates invasiveness of melanoma cells by matrix metallopeptidase 2. Dahal U, Kang L, Gupta M*. Melanoma Res. 2019 Feb 11. doi: 10.1097/CMR.0000000000000580.
2. Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma. Han JJ, O'byrne M, Stenson MJ, Maurer MJ, Wellik LE, Feldman AL, McPhail ED, Witzig TE, Gupta M*. Blood cancer journal. 2018; 8(11):110.
3. Elevated GLI3 expression in germinal center diffuse large B cell lymphoma.Han W, Ibarra G, Gupta M, Yin Y, Elsawa SF. Leukemia & lymphoma. 2018; :1-3
4. Anchimerically Activated ProTides as Inhibitors of Cap-Dependent Translation and Inducers of Chemosensitization in Mantle Cell Lymphoma. Okon A, Han J, Dawadi S, Demosthenous C, Aldrich CC, Gupta M*, Wagner CR*. Journal of medicinal chemistry. 2017; 60(19):8131-8144.
5. Long non-coding RNA profile in mantle cell lymphoma identifies a functional lncRNA ROR1-AS1 associated with EZH2/PRC2 complex.Hu G, Gupta SK, Troska TP, Nair A, Gupta M*.Oncotarget. 2017; 8(46):80223-80234.
6. Comprehensive serum cytokine analysis identifies IL-1RA and soluble IL-2Rα as predictors of event-free survival in T-cell lymphoma. Gupta M*, Stenson M, O'Byrne M, Maurer MJ, Habermann T, Cerhan JR, Weiner GW, Witzig TE . Annals of oncology: 2016; 27(1):165-72.
7. Loss of function mutations in PTPN6 promote STAT3 deregulation via JAK3 kinase in diffuse large B-cell lymphoma.Demosthenous C, Han JJ, Hu G, Stenson M, Gupta M*.Oncotarget. 2015; 6(42):44703-13.
8. The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma. *Witzig TE, Reeder C, Han JJ, LaPlant B, Stenson M, Tun HW, Macon W, Ansell SM, Habermann TM, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Colgan JP, Markovic S, Nowakowski GS, Gupta M*.Blood. 2015; 126(3):328-35.
9. Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma.Demosthenous C, Han JJ, Stenson MJ, Maurer MJ, Wellik LE, Link B, Hege K, Dogan A, Sotomayor E, Witzig T, Gupta M*. Oncotarget. 2015; 6(11):9488-501.
10. Elevated monoclonal and polyclonal serum immunoglobulin free light chain as prognostic factors in B- and T-cell non-Hodgkin lymphoma. Witzig TE, Maurer MJ, Habermann TM, Link BK, Micallef IN, Nowakowski GS, Ansell SM, Colgan JP, Inwards DJ, Porrata LF, Markovic SN, Johnston PB, Lin Y, Thompson C, Gupta M, Katzmann JA, Cerhan JR. American journal of hematology. 2014;89(12):1116-20. NIHMSID: NIHMS665185.
11. The long non-coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c-Myc translation.Hu G, Lou Z, Gupta M*. PloS one. 2014; 9(9):e107016.
12. Elevated soluble IL-2Rα, IL-8, and MIP-1β levels are associated with inferior outcome and are independent of MIPI score in patients with mantle cell lymphoma.Sonbol MB, Maurer MJ, Stenson MJ, Allmer C, LaPlant BR, Weiner GJ, Macon WR, Cerhan JR, *Witzig TE, Gupta M*. American journal of hematology. 2014; 89(12): E223-7. NIHMSID:
13. Elevated serum monoclonal and polyclonal free light chains and interferon inducible protein-10 predicts inferior prognosis in untreated diffuse large B-cell lymphoma. Witzig TE, Maurer MJ, Stenson MJ, Allmer C, Macon W, Link B, Katzmann JA, Gupta M*. American journal of hematology. 2014;89(4):417-22. NIHMSID: NIHMS586329
14. Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B-cell lymphoma: implications for epigenetic therapy. Witzig TE, Hu G, Offer SM, Wellik LE, Han JJ, Stenson MJ, Dogan A, Diasio RB, Gupta M*. Leukemia. 2014; 28(1):147-54. NIHMSID: NIHMS575068
15. A novel missense (M206K) STAT3 mutation in diffuse large B cell lymphoma deregulates STAT3 signaling. Hu G, Witzig TE, Gupta M*. PloS one. 2013; 8(7):e67851.
16. A phase I trial of immunostimulatory CpG 7909 oligodeoxynucleotide and 90 yttrium ibritumomab tiuxetan radioimmunotherapy for relapsed B-cell non-Hodgkin lymphoma. Witzig TE, Wiseman GA, Maurer MJ, Habermann TM, Micallef IN, Nowakowski GS, Ansell SM, Colgan JP, Inwards DJ, Porrata LF, Link BK, Zent CS, Johnston PB, Shanafelt TD, Allmer C, Asmann YW, Gupta M, Ballas ZK, Smith BJ, Weiner GJ. American journal of hematology. 2013; 88(7):589-93. NIHMSID: NIHMS503041
17. Lack of JAK2 activating non-synonymous mutations in diffuse large B-cell tumors: JAK2 deregulation still unexplained.Witzig TE, Price-Troska TL, Stenson MJ, Gupta M*.Leukemia & lymphoma. 2013; 54(2):397-9. NIHMSID: NIHMS558679
18. Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP. *Gupta M, Maurer MJ, Wellik LE, Law ME, Han JJ, Ozsan N, Micallef IN, Dogan A, Witzig TE. Blood. 2012; 120(22):4400-6.
19. t(X;14)(p11;q32) in MALT lymphoma involving GPR34 reveals a role for GPR34 in tumor cell growth. Ansell SM, Akasaka T, McPhail E, Manske M, Braggio E, Price-Troska T, Ziesmer S, Secreto F, Fonseca R, Gupta M, Law M, Witzig TE, Dyer MJ, Dogan A, Cerhan JR, Novak AJ. Blood. 2012; 120(19):3949-57.
20.Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapy. Gupta M*, Han JJ, Stenson M, Wellik L, Witzig TE. Leukemia. 2012; 26(6):1356-64. NIHMSID: NIHMS45401
21. Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation. Gupta M*, Han JJ, Stenson M, Maurer M, Wellik L, Hu G, Ziesmer S, Dogan A, Witzig TE. Blood. 2012; 119(12):2844-53.
22. Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies. Gupta M, Hendrickson AE, Yun SS, Han JJ, Schneider PA, Koh BD, Stenson MJ, Wellik LE, Shing JC, Peterson KL, Flatten KS, Hess AD, Smith BD, Karp JE, Barr S, Witzig TE, Kaufmann SH. Blood. 2012; 119(2):476-87.
23. Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas. Witzig TE, Tang H, Micallef IN, Ansell SM, Link BK, Inwards DJ, Porrata LF, Johnston PB, Colgan JP, Markovic SN, Nowakowski GS, Thompson CA, Allmer C, Maurer MJ, Gupta M, Weiner G, Hohl R, Kurtin PJ, Ding H, Loegering D, Schneider P, Peterson K, Habermann TM, Kaufmann SH. Blood. 2011; 118(18):4882-9.
24. Elevated serum free light chains are associated with event-free and overall survival in two independent cohorts of patients with diffuse large B-cell lymphoma. Maurer MJ, Micallef IN, Cerhan JR, Katzmann JA, Link BK, Colgan JP, Habermann TM, Inwards DJ, Markovic SN, Ansell SM, Porrata LF, Johnston PB, Nowakowski GS, Thompson CA, Gupta M, Syrbu SI, Kurtin PJ, Macon WR, Nikcevich DA, Witzig TE. Journal of clinical oncology. 2011; 29(12):1620-6.
25. Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Ansell SM, Tang H, Kurtin PJ, Koenig PA, Inwards DJ, Shah K, Ziesmer SC, Feldman AL, Rao R, Gupta M, Erlichman C, Witzig TE. The Lancet. Oncology. 2011; 12(4):361-8. NIHMSID: NIHMS287780
26. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma.Witzig TE, Reeder CB, LaPlant BR, Gupta M, Johnston PB, Micallef IN, Porrata LF, Ansell SM, Colgan JP, Jacobsen ED, Ghobrial IM, Habermann TM. Leukemia. 2011; 25(2):341-7. NIHMSID: NIHMS224659
27. Signal transduction inhibitor therapy for lymphoma. Witzig TE, Gupta M. American Society of Hematology. Education Program. Hematology 2010 :265-70. NIHMSID: NIHMS454012.
28. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Gupta M, Ansell SM, Novak AJ, Kumar S, Kaufmann SH, Witzig TE. Blood. 2009; 114(14):2926-35.
29. A proliferation-inducing ligand mediates follicular lymphoma B-cell proliferation and cyclin D1 expression through phosphatidylinositol 3-kinase-regulated mammalian target of rapamycin activation.Gupta M, Dillon SR, Ziesmer SC, Feldman AL, Witzig TE, Ansell SM, Cerhan JR, Novak AJ. Blood. 2009; 113(21):5206-16.
30. Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation. Gupta SK, Gupta M,Hoffman B, Liebermann DA. Oncogene. 2006; 25(40):5537-46.
31. Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition. Gupta M, Gupta SK, Hoffman B, Liebermann DA. The Journal of biological chemistry. 2006 ;281(26):17552
32. Hematopoietic cells from Gadd45a- and Gadd45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis. Gupta M, Gupta SK, Balliet AG, Hollander MC, Fornace AJ, Hoffman B, Liebermann DA. Oncogene. 2005; 24(48):7170-9.
33. BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells. Chu S, Holtz M, Gupta M, Bhatia R. Blood. 2004; 103(8):3167-74.
34. In vitro resistance of leukaemic blasts to prednisolone in bcr-abl positive childhood acute lymphoblastic leukaemia. Gupta M, Kumar A, Dabadghao S. The Indian journal of medical research. 2002;116:268-72.
35. Resistance of bcr-abl-positive acute lymphoblastic leukemia to daunorubicin is not mediated by mdr1 gene expression. Gupta M, Kumar A, Dabadghao S. American journal of hematology. 2002; 71(3):172-6.
36. Drug sensitivity assay for leukaemic cells by flow cytometry. Gupta M, Naik S, Pandey CM, Dabadghao S. The Indian journal of medical research. 2002; 115:260-4.