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    Alan G Rosmarin MD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMedicine
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-334-7433
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology

        Overview 
        Narrative

        ALAN ROSMARIN 07Education:

        • A.B.,Vassar College, 1977
        • M.D., UMDNJ – Rutgers Medical School, 1981
        • M.A. (Hon.), Brown University, 1998

        Post-Graduate Training:

        • Resident in Internal Medicine, Beth Israel Hospital/Harvard Medical School, 1981-1984
        • Clinical Fellow in Hematology/Oncology, Beth Israel Hospital, Boston, 1984-1985
        • Research Fellow, Harvard Medical School, Boston, 1985-1987

        Honors and Awards:

        • Phi Beta Kappa, Junior Year, 1976
        • Mary Pemberton Nourse Fellowship in Medicine, 1977
        • Alpha Omega Alpha, Junior Year, 1980
        • National Institutes of Health, National Research Service Award, 1984
        • National Institutes of Health, Physician Scientist Award, 1985
        • Beth Israel Hospital, Basic Research Service Award, 1986
        • Harvard Medical School, Milton Fund Award, 1987
        • American Federation for Clinical Research – Henry Christian Award, 1992
        • Brown University, Master of Arts, ad eundem, 1998

        Board Certification:

        • American Board of Internal Medicine, 1984
        • American Board of Internal Medicine (Hematology), 1986
        • American Board of Internal Medicine (Oncology), 1987

        Myeloid cells (granulocytes and monocytes) are critical for innate immunity and the inflammatory response. Differentiation of myeloid cells from hematopoietic stem cells is tightly regulated, and abnormalities in myeloid differentiation result in leukemia and myelodysplastic syndromes. Gene expression is tightly controlled during normal myeloid differentiation, and abnormalities of transcription factors underlie many forms of leukemia.1 Interests of the laboratory include the regulation of gene transcription in myeloid cells by the ets-related transcription factor, GA-Binding Protein (GABP), and the role of GABP in control of the cell cycle.

        beta cells ROSMARINGABP is the only obligate multimeric member of the etsfamily of transcription factors. This tetrameric transcription factor includes two distinct proteins: GABPa binds to DNA through its ets domain, and it recruits the unrelated protein, GABPb, which contains a transcription activation domain. GABPaalso includes a Pointed domain, through which it binds the transcription co-activator, p300.2

        cell group ROSMARINGABP regulates the transcription of several important myeloid genes, including CD18 (b2 leukocyte integrin),a4 integrin, neutrophil elastase, and lysozyme. The promoter of the leukocyte integrin, CD18, is bound and activated by GABP in myeloid cells, and GABP is required for transcriptional activation of CD18 in response to retinoic acid.3,4 We identified an enhanceosome, which includes GABP, p300, and retinoic acid receptors, that forms on the CD18 promoter in the presence of retinoic acid; this is the first known retinoic acid-responsive enhanceosome.5 Because abnormalities of retinoic acid receptors cause acute promyelocytic leukemia, these observations suggest that GABP participates in the aberrant differentiation associated with certain forms of leukemia.

        Absence of murine Gabpacauses early embryonic lethality, so we generated mice in which we can conditionally disrupt the encoding gene, Gabpa. Disruption of Gabpa dramatically reduces myeloid cells in the peripheral blood and bone marrow. Gabpanull cells contribute poorly to the myeloid compartment, and in vitro and in vivo studies suggest that GABP is required for both proliferation and differentiation of myeloid cells.

        cell activity ROSMARINWe generated mouse embryo fibroblasts (MEFs) from floxed Gabpa mice. In vitro disruption of Gabpa causes profound cell cycle arrest as the cells fail to enter S phase. Disruption of Gabpa reduces transcription of the genes that encode DNA Polymerase aand Thymidylate synthase, which are required for DNA synthesis, and Skp2, an E3 ubiquitin ligase that controls protein levels of the Cyclin dependent kinase inhibitors, p21 and p27. Serum stimulates transcription of Gabpa in growth-arrested cells, and expression of Gabpa is sufficient to induce cell cycle entry, even in the absence of serum stimulation. Unexpectedly, GABP regulates the cell cycle without altering expression of D-type cyclins, Cdks, Retinoblastoma (Rb) protein, and E2Fs. These findings indicate that GABP regulates a novel pathway to cell cycle entry that is independent of the canonical Cyclin D/Cdk/Rb/E2F pathway.6


        1Rosmarin AG, Yang Z, Resendes KK. Transcriptional Regulation In Myelopoiesis: Hematopoietic Fate Choice, Myeloid Differentiation, And Leukemogenesis, Experimental Hematology, 33: 131-143, 2005.

        2Rosmarin AG, Resendes KK, Yang Z, McMillan J, Fleming SL. GA Binding Protein (GABP) Transcription Factor: A Review - GABP as an Integrator of Intracellular Signaling and Protein-Protein Interactions. Blood Cells, Molecules, and Diseases 32: 143-154, 2004.

        3 Bush TS, St. Coeur M, Resendes KK, Rosmarin AG. GA Binding Protein (GABP) and Sp1 are required, along with Retinoid Receptors to mediate retinoic acid responsiveness of CD18 (β2 Leukocyte Integrin): a novel mechanism of transcriptional regulation in myeloid cells.Blood, 101:311-317, 2003.

        4 Resendes KK, Rosmarin AG. Sp1 Control of Gene Expression in Myeloid Cells. Critical Reviews in Eukaryotic Gene Expression. 14:171-181, 2004.

        5 Resendes KK, Rosmarin AG. GABP and p300 are essential components of a retinoic acid induced enhanceosome in myeloid cells. Molecular and Cellular Biology, 26:3060-3070, 2006.

        6 Yang Z-Y, Mott S, Rosmarin AG. The ets transcription factor GABP is required for cell cycle progression. Nature Cell Biology, 9:339-346, 2007.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Yang ZF, Zhang H, Ma L, Peng C, Chen Y, Wang J, Green MR, Li S, Rosmarin AG. GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2. Proc Natl Acad Sci U S A. 2013 Feb 5; 110(6):2312-7.
          View in: PubMed
        2. Zhu XJ, Yang ZF, Chen Y, Wang J, Rosmarin AG. PU.1 Is Essential for CD11c Expression in CD8(+)/CD8(-) Lymphoid and Monocyte-Derived Dendritic Cells during GM-CSF or FLT3L-Induced Differentiation. PLoS One. 2012; 7(12):e52141.
          View in: PubMed
        3. Cerny J, Yu H, Ramanathan M, Raffel GD, Walsh WV, Fortier N, Shanahan L, O'Rourke E, Bednarik J, Barton B, Kroll-Desrosiers A, Hao S, Woda B, Hutchinson L, M Evens A, Rosmarin AG, Nath R. Expression of CD25 independently predicts early treatment failure of acute myeloid leukaemia (AML). Br J Haematol. 2012 Nov 1.
          View in: PubMed
        4. Cerny J, Rosmarin AG. Why does my patient have leukocytosis? Hematol Oncol Clin North Am. 2012 Apr; 26(2):303-19.
          View in: PubMed
        5. Reagan JL, Rosmarin A, Butera JN, Nadeem A, Schiffman FJ, Sikov WM, Winer E, Mega AE. Phase I trial examining addition of gemcitabine to CHOP in intermediate grade NHL. Cancer Chemother Pharmacol. 2011 Oct; 68(4):1075-80.
          View in: PubMed
        6. Yang ZF, Drumea K, Cormier J, Wang J, Zhu X, Rosmarin AG. GABP transcription factor is required for myeloid differentiation, in part, through its control of Gfi-1 expression. Blood. 2011 Aug 25; 118(8):2243-53.
          View in: PubMed
        7. Strother RM, Gregory KM, Pastakia SD, Were P, Tenge C, Busakhala N, Jakait B, Schellhase EM, Rosmarin AG, Loehrer PJ. Retrospective analysis of the efficacy of gemcitabine for previously treated AIDS-associated Kaposi's sarcoma in western Kenya. Oncology. 2010; 78(1):5-11.
          View in: PubMed
        8. Peng C, Chen Y, Yang Z, Zhang H, Osterby L, Rosmarin AG, Li S. PTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in mice. Blood. 2010 Jan 21; 115(3):626-35.
          View in: PubMed
        9. Drumea K, Yang ZF, Rosmarin A. Retinoic acid signaling in myelopoiesis. Curr Opin Hematol. 2008 Jan; 15(1):37-41.
          View in: PubMed
        10. Yang ZF, Mott S, Rosmarin AG. The Ets transcription factor GABP is required for cell-cycle progression. Nat Cell Biol. 2007 Mar; 9(3):339-46.
          View in: PubMed
        11. Resendes KK, Rosmarin AG. GA-binding protein and p300 are essential components of a retinoic acid-induced enhanceosome in myeloid cells. Mol Cell Biol. 2006 Apr; 26(8):3060-70.
          View in: PubMed
        12. Rosmarin AG, Yang Z, Resendes KK. Transcriptional regulation in myelopoiesis: Hematopoietic fate choice, myeloid differentiation, and leukemogenesis. Exp Hematol. 2005 Feb; 33(2):131-43.
          View in: PubMed
        13. Rosmarin AG, Resendes KK, Yang Z, McMillan JN, Fleming SL. GA-binding protein transcription factor: a review of GABP as an integrator of intracellular signaling and protein-protein interactions. Blood Cells Mol Dis. 2004 Jan-Feb; 32(1):143-54.
          View in: PubMed
        14. Resendes KK, Rosmarin AG. Sp1 control of gene expression in myeloid cells. Crit Rev Eukaryot Gene Expr. 2004; 14(3):171-81.
          View in: PubMed
        15. Bush TS, St Coeur M, Resendes KK, Rosmarin AG. GA-binding protein (GABP) and Sp1 are required, along with retinoid receptors, to mediate retinoic acid responsiveness of CD18 (beta 2 leukocyte integrin): a novel mechanism of transcriptional regulation in myeloid cells. Blood. 2003 Jan 1; 101(1):311-7.
          View in: PubMed
        16. Gyrd-Hansen M, Krag TO, Rosmarin AG, Khurana TS. Sp1 and the ets-related transcription factor complex GABP alpha/beta functionally cooperate to activate the utrophin promoter. J Neurol Sci. 2002 May 15; 197(1-2):27-35.
          View in: PubMed
        17. Khanna-Gupta A, Zibello T, Simkevich C, Rosmarin AG, Berliner N. Sp1 and C/EBP are necessary to activate the lactoferrin gene promoter during myeloid differentiation. Blood. 2000 Jun 15; 95(12):3734-41.
          View in: PubMed
        18. Beckwith C, Butera J, Sadaniantz A, King TC, Fingleton J, Rosmarin AG. Diagnosis in oncology. Case 1: primary transmural cardiac lymphoma. J Clin Oncol. 2000 May; 18(9):1996-7.
          View in: PubMed
        19. Luo M, Shang J, Yang Z, Simkevich CP, Jackson CL, King TC, Rosmarin AG. Characterization and localization to chromosome 7 of psihGABPalpha, a human processed pseudogene related to the ets transcription factor, hGABPalpha. Gene. 1999 Jun 24; 234(1):119-26.
          View in: PubMed
        20. Khurana TS, Rosmarin AG, Shang J, Krag TO, Das S, Gammeltoft S. Activation of utrophin promoter by heregulin via the ets-related transcription factor complex GA-binding protein alpha/beta. Mol Biol Cell. 1999 Jun; 10(6):2075-86.
          View in: PubMed
        21. Nuchprayoon I, Shang J, Simkevich CP, Luo M, Rosmarin AG, Friedman AD. An enhancer located between the neutrophil elastase and proteinase 3 promoters is activated by Sp1 and an Ets factor. J Biol Chem. 1999 Jan 8; 274(2):1085-91.
          View in: PubMed
        22. Rosmarin AG, Luo M, Caprio DG, Shang J, Simkevich CP. Sp1 cooperates with the ets transcription factor, GABP, to activate the CD18 (beta2 leukocyte integrin) promoter. J Biol Chem. 1998 May 22; 273(21):13097-103.
          View in: PubMed
        23. Nuchprayoon I, Simkevich CP, Luo M, Friedman AD, Rosmarin AG. GABP cooperates with c-Myb and C/EBP to activate the neutrophil elastase promoter. Blood. 1997 Jun 15; 89(12):4546-54.
          View in: PubMed
        24. Safran H, King TP, Choy H, Hesketh PJ, Wolf B, Altenhein E, Sikov W, Rosmarin A, Akerley W, Radie-Keane K, Cicchetti G, Lopez F, Bland K, Wanebo HJ. Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study. J Clin Oncol. 1997 Mar; 15(3):901-7.
          View in: PubMed
        25. Rosmarin AG, Caprio DG, Simkevich CP. Scanning mutagenesis to localize DNA-protein interactions. Biotechniques. 1997 Mar; 22(3):434-6.
          View in: PubMed
        26. Safran H, King T, Choy H, Gollerkeri A, Kwakwa H, Lopez F, Cole B, Myers J, Tarpey J, Rosmarin A. p53 mutations do not predict response to paclitaxel/radiation for nonsmall cell lung carcinoma. Cancer. 1996 Sep 15; 78(6):1203-10.
          View in: PubMed
        27. Rosmarin AG, Caprio DG, Kirsch DG, Handa H, Simkevich CP. GABP and PU.1 compete for binding, yet cooperate to increase CD18 (beta 2 leukocyte integrin) transcription. J Biol Chem. 1995 Oct 6; 270(40):23627-33.
          View in: PubMed
        28. Lasky SR, Iwata K, Rosmarin AG, Caprio DG, Maizel AL. Differential regulation of JunD by dihydroxycholecalciferol in human chronic myelogenous leukemia cells. J Biol Chem. 1995 Aug 25; 270(34):19676-9.
          View in: PubMed
        29. Rosmarin AG, Caprio D, Levy R, Simkevich C. CD18 (beta 2 leukocyte integrin) promoter requires PU.1 transcription factor for myeloid activity. Proc Natl Acad Sci U S A. 1995 Jan 31; 92(3):801-5.
          View in: PubMed
        30. Rosmarin AG, Levy R, Tenen DG. Cloning and analysis of the CD18 promoter. Blood. 1992 May 15; 79(10):2598-604.
          View in: PubMed
        31. Mazur EM, Rosmarin AG, Sohl PA, Newton JL, Narendran A. Analysis of the mechanism of anagrelide-induced thrombocytopenia in humans. Blood. 1992 Apr 15; 79(8):1931-7.
          View in: PubMed
        32. Pahl HL, Rosmarin AG, Tenen DG. Characterization of the myeloid-specific CD11b promoter. Blood. 1992 Feb 15; 79(4):865-70.
          View in: PubMed
        33. Rosmarin AG, Weil SC, Rosner GL, Griffin JD, Arnaout MA, Tenen DG. Differential expression of CD11b/CD18 (Mo1) and myeloperoxidase genes during myeloid differentiation. Blood. 1989 Jan; 73(1):131-6.
          View in: PubMed
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