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).

Selected References:

1. 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 (In Press)

2. 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           
3. 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 L, Mollenhauer J, Thompson R, 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
4. 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
5. 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
6. 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
7. 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