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    Lucio H Castilla PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentProgram in Molecular Medicine
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-622
    Worcester MA 01605
    Phone508-856-3281
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - School of Medicine
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentProgram in Gene Function and Expression

        Overview 
        Narrative

        Academic Background

        Lucio Castilla received his B. S. from the University of Buenos Aires in 1988, and his Ph.D. from the University of Michigan in 1995. He was a postdoctoral fellow in the National Human Genome Research Institute, at the National Institutes of Health, from 1995 to 2000. He joined the University of Massachusetts Medical School, in the Program of Gene Function and Expression, as an Assistant Professor in 2000. He is the recipient of a Special Fellow Award from the Leukemia and Lymphoma Society (1999) and an AACR-Sidney Kimmel Symposium for Cancer Research Scholar Award (2002). Dr. Castilla is a Leukemia and Lymphoma Society Scholar (2007-2012).

        Genetics of Leukemia, Mouse Models

        Lucio Castilla, Ph.D.The goal of our laboratory is to understand the molecular mechanisms of leukemia development. Leukemia arises from the abnormal expansion of hematopoietic stem cells that have acquired multiple genetic alterations that block differentiation programs and provide proliferation and survival capacity. The dimeric transcription factor “core-binding-factor” (CBF) is a master regulator of gene expression during development and differentiation. Genetic alterations in either CBF subunit, RUNX1 or CBFß, have been associated with human leukemia. For example, acute myeloid leukemia (AML) samples with chromosome 16 inversion express the fusion gene CBFB-MYH11. We and others have shown that Cbfb-MYH11 expression hinders multi-lineage differentiation. We have recently used a conditional Cbfb-MYH11 knock-in mouse model to show that the fusion gene also creates an abnormal myeloid progenitor that progress to AML upon the accumulation of cooperating mutations that provide proliferation and/or survival advantage (see Figure).

        One line of our research uses conditional knock-in and knock-out strategies to better understand the role of CBF factors in hematopoietic stem cells and the alterations induced by Cbfb-MYH11 expression in this compartment as well as during multi-lineage differentiation. Second, we are characterizing the contribution of other de-regulated genes that collaborate with Cbfb-MYH11 in leukemogenesis. We use retroviral insertional mutagenesis in mice expressing Cbfb-MYH11 to identify candidate cooperating genes. We are particularly interested on one of these factors, the pleomorphic adenoma like-2 gene (PlagL2), and are studying its role in normal and malignant hematopoiesis. Third, the leukemic cells are a heterogeneous group of cells at different stages of differentiation. Few of these cells, called leukemia-initiating cells, hold the capacity to expand indefinitely and recreate the disease. We focus part of our efforts on characterizing the CBF leukemia-initiating cells, with the goal of identifying small molecules that inhibit Cbfb-MYH11 function and may be used in the design of improved therapy.

        Figure


        Rotation Projects

        Potential Rotation Projects

         

        1. Role of core binding factors on hematopoietic stem cell function and survival. We use molecular pharmacologic and functional approaches to study the role of the RUNX factors in self renewal and proliferation of hematopoietic stem and progenitor cells, using genetically modified mice and human progenitor cells.

         

        2. Study the molecular mechanism of leukemia initiation and maintenance. Transcription factors and components of cytokine signaling are frequently mutated in human cancer, including leukemia. These mutations deregulate the proliferation, differentiation and survival of hematopoietic stem cells. We study the role of members of RUNX and RAS protein families in the function of hematopoietic stem cell function, pre-leukemic progenitors, and leukemia-initiating cells.

         

        3. Translational research: Recent evidence suggests that inhibition of pathways activated by gene mutations can be used to eliminate leukemia cells, and not affecting normal cells. We use small molecule inhibitors of leukemia oncogenes to test whether repression of activated pathways hinder survival of leukemia initiating cells, and eliminate leukemia. We use a combination of mouse models and human leukemia cells to test the efficacy, specificity and toxicity of candidate inhibitors, as single agents or in combination with first line leukemia drugs.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Naipauer J, Gattelli A, Degese MS, Slomiansky V, Wertheimer E, Lamarre J, Castilla L, Abba M, Kordon EC, Coso OA. The use of alternative polyadenylation sites renders ß1- integrin mRNA isoforms with differential stability during mammary gland development. Biochem J. 2013 Jun 21.
          View in: PubMed
        2. Pulikkan JA, Madera D, Xue L, Bradley P, Landrette SF, Kuo YH, Abbas S, Zhu LJ, Valk P, Castilla LH. Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling. Blood. 2012 Jul 26; 120(4):868-79.
          View in: PubMed
        3. Kuo YH, Zaidi SK, Gornostaeva S, Komori T, Stein GS, Castilla LH. Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice. Blood. 2009 Apr 2; 113(14):3323-32.
          View in: PubMed
        4. Castilla LH. C/EBPalpha in leukemogenesis: a matter of being in the right place with the right signals. Cancer Cell. 2008 Apr; 13(4):289-91.
          View in: PubMed
        5. Kuo YH, Gerstein RM, Castilla LH. Cbfbeta-SMMHC impairs differentiation of common lymphoid progenitors and reveals an essential role for RUNX in early B-cell development. Blood. 2008 Feb 1; 111(3):1543-51.
          View in: PubMed
        6. Zhao L, Cannons JL, Anderson S, Kirby M, Xu L, Castilla LH, Schwartzberg PL, Bosselut R, Liu PP. CBFB-MYH11 hinders early T-cell development and induces massive cell death in the thymus. Blood. 2007 Apr 15; 109(8):3432-40.
          View in: PubMed
        7. Heilman SA, Kuo YH, Goudswaard CS, Valk PJ, Castilla LH. Cbfbeta reduces Cbfbeta-SMMHC-associated acute myeloid leukemia in mice. Cancer Res. 2006 Dec 1; 66(23):11214-8.
          View in: PubMed
        8. Gattelli A, Zimberlin MN, Meiss RP, Castilla LH, Kordon EC. Selection of early-occurring mutations dictates hormone-independent progression in mouse mammary tumor lines. J Virol. 2006 Nov; 80(22):11409-15.
          View in: PubMed
        9. Kuo YH, Landrette SF, Heilman SA, Perrat PN, Garrett L, Liu PP, Le Beau MM, Kogan SC, Castilla LH. Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Cancer Cell. 2006 Jan; 9(1):57-68.
          View in: PubMed
        10. Landrette SF, Kuo YH, Hensen K, Barjesteh van Waalwijk van Doorn-Khosrovani S, Perrat PN, Van de Ven WJ, Delwel R, Castilla LH. Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11. Blood. 2005 Apr 1; 105(7):2900-7.
          View in: PubMed
        11. Gattelli A, Cirio MC, Quaglino A, Schere-Levy C, Martinez N, Binaghi M, Meiss RP, Castilla LH, Kordon EC. Progression of pregnancy-dependent mouse mammary tumors after long dormancy periods. Involvement of Wnt pathway activation. Cancer Res. 2004 Aug 1; 64(15):5193-9.
          View in: PubMed
        12. Castilla LH, Perrat P, Martinez NJ, Landrette SF, Keys R, Oikemus S, Flanegan J, Heilman S, Garrett L, Dutra A, Anderson S, Pihan GA, Wolff L, Liu PP. Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. Proc Natl Acad Sci U S A. 2004 Apr 6; 101(14):4924-9.
          View in: PubMed
        13. Kundu M, Chen A, Anderson S, Kirby M, Xu L, Castilla LH, Bodine D, Liu PP. Role of Cbfb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene Cbfb-MYH11. Blood. 2002 Oct 1; 100(7):2449-56.
          View in: PubMed
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