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Lucio H Castilla PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentMolecular, Cell and Cancer Biology
AddressUniversity of Massachusetts Medical School
364 Plantation Street, LRB-622
Worcester MA 01605
Phone508-856-3281
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentBiochemistry and Molecular Pharmacology

    InstitutionUMMS - School of Medicine
    DepartmentMolecular, Cell and Cancer Biology

    InstitutionUMMS - School of Medicine
    DepartmentProgram in Molecular Medicine

    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


    Collapse Biography 
    Collapse education and training
    University of Buenos Aires, Buenos Aires, BA, ArgentinaMSGenetics
    University of Michigan, Ann Arbor, Ann Arbor, MI, United StatesPHDGenetics

    Collapse Overview 
    Collapse overview


     



    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


    Collapse 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.



    Collapse Post Docs


    The Castilla laboratory is accepting applications for postdoctoral positions. The candidates should be close to or have recently graduated with a Ph.D. or M.D./Ph.D. degree (within 1 year) in the fields of Cancer Biology, Genetics, Biochemistry, Cell Biology or related field. The candidates must also have a proven track record of productivity and research experience. Previous experience using immunocompromised and transgenic mice, in vitro and in vivo assays with small molecules or nanoparticles, or hematopoietic stem cells is preferred.



    We are looking for highly motivated candidates with excellent communication skills, and able to work independently and in cooperation with other members of the laboratory.



    Applicants should send their CV, a cover letter summarizing background and research interests, and three letters of references by electronic mail to:



    Dr. Lucio H. Castilla, Associate Professor


    University of Massachusetts Medical School


    Lucio.Castilla@umassmed.edu


     




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Pulikkan JA, Hegde M, Ahmad HM, Belaghzal H, Illendula A, Yu J, O'Hagan K, Ou J, Muller-Tidow C, Wolfe SA, Zhu LJ, Dekker J, Bushweller JH, Castilla LH. CBFß-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia. Cell. 2018 Aug 23; 174(5):1325. PMID: 30142347.
      View in: PubMed
    2. Pulikkan JA, Hegde M, Ahmad HM, Belaghzal H, Illendula A, Yu J, O'Hagan K, Ou J, Muller-Tidow C, Wolfe SA, Zhu LJ, Dekker J, Bushweller JH, Castilla LH. CBFß-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia. Cell. 2018 Jun 28; 174(1):172-186.e21. PMID: 29958106.
      View in: PubMed
    3. Pulikkan JA, Castilla LH. Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid Leukemia. Front Oncol. 2018; 8:129. PMID: 29755956.
      View in: PubMed
    4. Ou J, Liu H, Yu J, Kelliher MA, Castilla LH, Lawson ND, Zhu LJ. ATACseqQC: a Bioconductor package for post-alignment quality assessment of ATAC-seq data. BMC Genomics. 2018 03 01; 19(1):169. PMID: 29490630.
      View in: PubMed
    5. Illendula A, Gilmour J, Grembecka J, Tirumala VSS, Boulton A, Kuntimaddi A, Schmidt C, Wang L, Pulikkan JA, Zong H, Parlak M, Kuscu C, Pickin A, Zhou Y, Gao Y, Mishra L, Adli M, Castilla LH, Rajewski RA, Janes KA, Guzman ML, Bonifer C, Bushweller JH. Corrigendum to: "Small Molecule Inhibitor of CBFß-RUNX Binding for RUNX Transcription Factor Driven Cancers" [EBioMedicine 8 (2016) 117-131]. EBioMedicine. 2017 11; 25:188. PMID: 29104075.
      View in: PubMed
    6. Choi A, Illendula A, Pulikkan JA, Roderick JE, Tesell J, Yu J, Hermance N, Zhu LJ, Castilla LH, Bushweller JH, Kelliher MA. RUNX1 is required for oncogenic Myb and Myc enhancer activity in T cell acute lymphoblastic leukemia. Blood. 2017 Aug 08. PMID: 28790107.
      View in: PubMed
    7. Castilla LH, Bushweller JH. Molecular Basis and Targeted Inhibition of CBFß-SMMHC Acute Myeloid Leukemia. Adv Exp Med Biol. 2017; 962:229-244. PMID: 28299661.
      View in: PubMed
    8. Illendula A, Gilmour J, Grembecka J, Tirumala VS, Boulton A, Kuntimaddi A, Schmidt C, Wang L, Pulikkan JA, Zong H, Parlak M, Kuscu C, Pickin A, Zhou Y, Gao Y, Mishra L, Adli M, Castilla LH, Rajewski RA, Janes KA, Guzman ML, Bonifer C, Bushweller JH. Small Molecule Inhibitor of CBFß-RUNX Binding for RUNX Transcription Factor Driven Cancers. EBioMedicine. 2016 Jun; 8:117-31. PMID: 27428424.
      View in: PubMed
    9. Recouvreux MS, Grasso EN, Echeverria PC, Rocha-Viegas L, Castilla LH, Schere-Levy C, Tocci JM, Kordon EC, Rubinstein N. RUNX1 and FOXP3 interplay regulates expression of breast cancer related genes. Oncotarget. 2016 Feb 09; 7(6):6552-65. PMID: 26735887.
      View in: PubMed
    10. Illendula A, Pulikkan JA, Zong H, Grembecka J, Xue L, Sen S, Zhou Y, Boulton A, Kuntimaddi A, Gao Y, Rajewski RA, Guzman ML, Castilla LH, Bushweller JH. Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFß-SMMHC delays leukemia in mice. Science. 2015 Feb 13; 347(6223):779-84. PMID: 25678665.
      View in: PubMed
    11. Xue L, Pulikkan JA, Valk PJ, Castilla LH. NrasG12D oncoprotein inhibits apoptosis of preleukemic cells expressing Cbfß-SMMHC via activation of MEK/ERK axis. Blood. 2014 Jul 17; 124(3):426-36. PMID: 24894773.
      View in: PubMed
    12. 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. PMID: 22613795.
      View in: PubMed
    13. Landrette SF, Madera D, He F, Castilla LH. The transcription factor PlagL2 activates Mpl transcription and signaling in hematopoietic progenitor and leukemia cells. Leukemia. 2011 Apr; 25(4):655-62. PMID: 21263445.
      View in: PubMed
    14. 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 02; 113(14):3323-32. PMID: 19179305.
      View in: PubMed
    15. 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. PMID: 18394549.
      View in: PubMed
    16. 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. PMID: 17940206.
      View in: PubMed
    17. 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. PMID: 17145866.
      View in: PubMed
    18. 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. PMID: 16413472.
      View in: PubMed
    19. 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. PMID: 15585652.
      View in: PubMed
    20. 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. PMID: 15044690.
      View in: PubMed
    21. Adya N, Castilla LH, Liu PP. Function of CBFbeta/Bro proteins. Semin Cell Dev Biol. 2000 Oct; 11(5):361-8. PMID: 11105900.
      View in: PubMed
    22. Castilla LH, Garrett L, Adya N, Orlic D, Dutra A, Anderson S, Owens J, Eckhaus M, Bodine D, Liu PP. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nat Genet. 1999 Oct; 23(2):144-6. PMID: 10508507.
      View in: PubMed
    23. Yang X, Castilla LH, Xu X, Li C, Gotay J, Weinstein M, Liu PP, Deng CX. Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development. 1999 Apr; 126(8):1571-80. PMID: 10079220.
      View in: PubMed
    24. Yamanaka R, Barlow C, Lekstrom-Himes J, Castilla LH, Liu PP, Eckhaus M, Decker T, Wynshaw-Boris A, Xanthopoulos KG. Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein epsilon-deficient mice. Proc Natl Acad Sci U S A. 1997 Nov 25; 94(24):13187-92. PMID: 9371821.
      View in: PubMed
    25. Castilla LH, Wijmenga C, Wang Q, Stacy T, Speck NA, Eckhaus M, Marín-Padilla M, Collins FS, Wynshaw-Boris A, Liu PP. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell. 1996 Nov 15; 87(4):687-96. PMID: 8929537.
      View in: PubMed
    26. Abel KJ, Brody LC, Valdes JM, Erdos MR, McKinley DR, Castilla LH, Merajver SD, Couch FJ, Friedman LS, Ostermeyer EA, Lynch ED, King MC, Welcsh PL, Osborne-Lawrence S, Spillman M, Bowcock AM, Collins FS, Weber BL. Characterization of EZH1, a human homolog of Drosophila Enhancer of zeste near BRCA1. Genomics. 1996 Oct 15; 37(2):161-71. PMID: 8921387.
      View in: PubMed
    27. Brody LC, Abel KJ, Castilla LH, Couch FJ, McKinley DR, Yin G, Ho PP, Merajver S, Chandrasekharappa SC, Xu J, et al. Construction of a transcription map surrounding the BRCA1 locus of human chromosome 17. Genomics. 1995 Jan 1; 25(1):238-47. PMID: 7774924.
      View in: PubMed
    28. Couch FJ, Castilla LH, Xu J, Abel KJ, Welcsh P, King SE, Wong L, Ho PP, Merajver S, Brody LC, et al. A YAC-, P1-, and cosmid-based physical map of the BRCA1 region on chromosome 17q21. Genomics. 1995 Jan 1; 25(1):264-73. PMID: 7774927.
      View in: PubMed
    29. Castilla LH, Couch FJ, Erdos MR, Hoskins KF, Calzone K, Garber JE, Boyd J, Lubin MB, Deshano ML, Brody LC, et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet. 1994 Dec; 8(4):387-91. PMID: 7894491.
      View in: PubMed
    30. Couch FJ, Kiousis S, Castilla LH, Xu J, Chandrasekharappa SC, Chamberlain JS, Collins FS, Weber BL. Characterization of 10 new polymorphic dinucleotide repeats and generation of a high-density microsatellite-based physical map of the BRCA1 region of chromosome 17q21. Genomics. 1994 Dec; 24(3):419-24. PMID: 7713491.
      View in: PubMed
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