Amit K. Verma, M.B.,B.S.
Key Words: cytokines, hematopoiesis, epigenetics, mds, leukemia, esophageal cancer, pancreatic cancer
1. Targeting signal transduction in hematologic malignancies: Cytokines play important roles in the regulation of normal hematopoiesis and a balance between the actions of hematopoietic growth factors and myelosuppressive factors is required for optimal production of different hematopoietic cell lineages. We study the role of MAP kinases in the regulation of hematopoiesis and have shown that the p38 MAPK signalling pathway is the dominant cytokine regulated inhibitory pathway in human hematopoiesis and is overactivated in MDS. The myelodysplastic syndromes (MDS) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias due to ineffective hematopoiesis. These preleukemic disorders are common causes of anemia in the elderly and are rapidly increasing in incidence. We have also demonstrated that the TGF-b pathways is overactivated in MDS. We are trying to study the molecular mechanisms that lead to the activation of these pathways in MDS and are using small molecule inhibitors in mouse models to target these pathways.
2. Epigenomic analysis of tumors: We are using high throughput assays to analyze DNA methylation across the genome and have optimized these assays to work with low amounts of DNA. We have successfully used these assays in conducting an integrative analysis of epigenetic and genetic alterations in MDS and esophageal cancer. We are now exploring alterations in DNA methylation in pancreatic cancer, myeloproliferative neoplasms and renal cell cancer.
3. Clinical studies in Myelodysplastic syndromes: We have a “center of excellence” clinic for patients with Myelodysplatic syndromes. We offer a variety of clinical trials for these patients (www.mdstreatment.com).
- Bhattacharyya S, Yu Y, Suzuki M, Campbell N, Mazdo J, Vasanthakumar A, Bhagat TD, Nischal S, Christopeit M, Parekh S, Steidl U, Godley L, Maitra A, Greally JM, Verma A.Genome wide hydroxymethylation tested using the HELP-GT assay shows redistribution in cancer.Nuc. Acid. Res. 2013;In Press
- Bartholdy B, Christopeit M, Will B, Mo Y, Barreyro L, Yu Y, Bhagat T, Okoye-Okafor U, Todorova T, Greally J, Levine RL, Melnick A, Verma A*, Steidl U*. A human hematopoietic stem cell-commitment related DNA cytosine methylation signature is prognostic for overall survival in acute myeloid leukemia Journal of Clinical Investigation 2013, (In Press) *Co-Corresponding.
- Bhagat T, Zhou L, Sokol L, Caceres G, Gundabolu K, Gordon S, Mantzaris I, Gligich O, Yu Y, Bhattacharyya S, Jing X, Polineni R, Tamari R, Bhatia K, Pellagatti A , Boultwood J, Kambhampati S, Steidl U, Stein C, Ju W, Liu G, Kenny P, List A, Bitzer M, Verma A. miR-21 mediates hematopoietic suppression in MDS by activating TGF-b signaling Blood 2013, (In Press) PMID: 23390194
- Yu Y, Mo Y, Liu H, Bhattacharyya S, Ebenezer D, Sundaravel S, Caces B, Ulaszek J, Artz A, Nischal S, Bhagat T, Bathon , Maqbool S, Suzuki M, Steidl U, Godley L, Skoultchi A, Greally J, Wickrema A, Verma A High resolution methylome analysis reveals widespread hypomethylation during human erythroid differentiation JBC 2013 (In Press) PMID: 23306203
- Heuck C, Mehta J, Bhagat T, Gundabolu K, Yu Y, Khan S, Chrysofakis G, Schinke C, Tariman J, Vickrey E, Pulliam N, Nischal S, Zhou L, Bhattacharya S, Meagher R, Hu C, Maqbool S, , Suzuki M, Parekh S, Reu F, Steidl U, Greally J, Verma A*, Singhal S* Co-Corresponding Myeloma is characterized by stage specific alterations in DNA methylation that occur early during myelomagenesis Journal of Immunology (In Press) 2013
- Wu W, Bhagat T, Yang X, Song J, Cheng Y, Agarwal R, Abraham J, Ibrahim S, Bartenstein M, Hussain Z, Suzuki M, Yu Y, Eng C, Greally J, Verma A*, Meltzer SJ* Co-Corresponding Hypomethylation of Noncoding DNA Regions and Overexpression of the Long Noncoding RNA, AFAP1-AS1, in Barrett’s Esophagus and Esophageal Adenocarcinoma Gastroenterology (In Press) 2013 PMID: 23333711
- Nischal S, Bhattacharyya S, Christopeit N, Yu Y, Zhou L, Bhagat T, Sohal S, Will B, Mo Y, Suzuki M, Pardanani A, McDevitt M, Maciejewski J, Melnick A, Greally J, Steidl U, Moliterno A, Verma A Methylome profiling reveals distinct alterations in phenotypic and mutational subgroups of myeloproliferative neoplasms Cancer Res, 2012 Dec 27. PMID: 23066032
- Will B, Zhou L, Vogler TO, Ben-Neriah S, Schinke C,Tamari R, Yu Y, Bhagat T, Bhattacharya S, Barreyro L, Heuck C, Mo Y, Parekh S, McMahon C, Pellagatti A, Boultwood J, Montagna C, Silverman L, Maciejewski J, Greally JM, Ye BH, List AF, Steidl C, Steidl U, Verma A Stem and progenitor cells in myelodysplastic syndromes show aberrant stage specific expansion and harbor genetic and epigenetic alterations, Blood 2012; 120(10):2076-86. PMID: 22753872
- Roth M, Will B, Simkin G, Narayanagari S, Barreyro L, Bartholdy B, Tamari R, Mitsiades CS, Verma A, Steidl U. Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation. Blood. 2012 May 24. PMID: 22627766
- Barta SK, Zou Y, Schindler J, Shenoy N, Bhagat TD, Steidl U, Verma A. Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia. Leuk Lymphoma. 2012 Apr 18. PMID: 22448921
- Zhou L, Opalinska J, Sohal D, Yu Y, Mo Y, Bhagat T, Abdel-Wahab O, Fazzari M, Figueroa M, Alencar C, Zhang J, Kanbhampati S, Parmar S, Nischal S, Heuck C, Suzuki M, Friedman E, Pellagatti A, Boultwood J, Steidl U, Sauthararajah Y, Yajnik V, Gore SD, Platanias LC, Levine R, Melnick A, Greally JM, Verma A. Aberrant epigenetic and genetic marks are seen in myelodysplastic leucocytes and reveal DOCK4 as a candidate pathogenic gene on chr7q. J Biol Chem. 2011 Apr 30. PMID: 21532034
- Alvarez H, Opalinska J, Zhou L, Sohal D, Fazzari M, Yu Y, Montagna C, Montgomery E, Canto M, Dunbar K, Wang J, Roa J, Mo Y, Bhagat T, Ramesh K, Cannizzaro, Mollenhauer, Thompson, Suzuki M, Meltzer S, Melnick A, Greally JM, Maitra A, Verma A Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis. PLOS Genetics 2011 Mar;7(3) PMID: 21483804
- L Zhou, C McMahon, T Bhagat, C Alencar, Y Yu, M Fazzari, D Sohal, C Heuck, K Gundabolu, C Ng, Y Mo, W Shen, A Wickrema, G Kong, E Friedman, L Sokol, G Mantzaris, A Pellagatti , J Boultwood, LC. Platanias. U Steidl, L Yan, JM Yingling, MM Lahn, A List, M Bitzer and A Verma Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Research 2011 Feb 1;71(3):955-63.PMID: 21189329
- Oda M., Glass J.L., Thompson R.F., Mo Y., Olivier E., Figueroa M.E., Selzer R.R., Richmond T.A., Zhang X., Dannenberg L., Green R., Melnick A., Hatchwell E., Bouhassira E., Verma A., Suzuki M., Greally J.M. High-resolution genome-wide cytosine methylation profiling with simultaneous copy number analysis and optimization for limited cell numbers. Nucleic Acids Res. 2009 Jul;37(12):3829-39. PMID: 19386619
- Sohal D, Yeatts A, Ye K, Pellagatti A, Zhou L, Pahanish P, Mo Y, Bhagat T, Mariadason J, Boultwood J, Melnick A, Greally JM, Verma A. Meta-analysis of microarray studies reveals a novel hematopoietic progenitor cell signature and demonstrates feasibility of inter-platform data integration. PLOS One 2008 Aug 13;3(8):e2965 PMID: 18698424
- Zhou L, Nguyen AN, Sohal D, Ma JY, Pahanish P, Gundabolu K, Hayman J, Chubak A, Mo Y, Bhagat T, Das B, Haghnazari E, Navas T, Parmar S, Kambhampati S, Pellagati A, Braunchweig I, Zhang YE, Wickrema A, Boultwood J, Platanias LC, Higgins LS, List A, Bitzer M, Verma A. Inhibition of Transforming Growth Factor beta receptor I kinase can stimulate hematopoiesis in MDS Blood 2008 Oct 15;112(8):3434-43 PMID: 18474728
- Navas T, Mohindru M, Estes M, Ma JY, Sokol L, Pahanish P, Parmar S, Haghnazari E, Zhou L, Collins RC, Kerr I, Nguyen A, Xu Y, Platanias LC, List AA, Higgins LS, Verma A. Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors Blood 2006, 15;108(13):4170-7 PMID: 16940419
- Verma A and List A Cytokine Targets in Myelodysplastic syndromes Current Hematology Reports 2005 Nov;4(6):429-35 PMID: 16232378
- Deonarain R, Verma A, Porter AC, Gewert DR, Platanias LC, Fish EN. Critical roles for IFN-beta in lymphoid development, myelopoiesis, and tumor development: links to tumor necrosis factor alpha. Proc Natl Acad SciU S A. 2003 Nov 11;100(23):13453-8 PMID: 14597717
- Verma A., Mohindru M., Deb D., Sassano A., Kambhampati S., Minucci S., Ravandi F., Kovakanalu D, Platanias L “Activation of the Rac1 and p38 MAP kinase pathway in response to Arsenic trioxide.” Journal of Biological Chemistry 22;277(47):44988-95 PMID: 12239215
- Verma A, Sassano A, Deb D, Wickrema, A., VanBesien K., and Platanias L. “Blockade of p38 MAP kinase reverses cytokine mediated inhibition in aplastic anemia.” Journal of Immunology2002, 168 (12) (Cutting edge section) PMID: 12055203
- Verma A, Deb D.K., Sassano A., Uddine S., Wickrema A., Varga and Platanias LC “Activation of the p38 mitogen activated protein kinase mediates suppressive effects of Type I interferons and transforming growth factor- on normal hematopoiesis.” Journal of Biological Chemistry2002, 277(10):7726-35 PMID: 11773065
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