Rafael C. Casellas, Ph.D.
Department of Hematopoietic Biology & Malignancy, Division of Cancer Medicine
Present Title & Affiliation
Dual/Joint/Adjunct Appointment
Professor, Department of Hematopoietic Biology and Malignancy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Professor, Department of Immunology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Research Interests
Antibody-based immunotherapies are among the most promising treatments against human malignancies. Chimeric antigen receptor (CAR) T cells and T cell engagers efficiently combine tumor antigen recognition by antibody variable domains (heavy and light chains) with T cell cytotoxicity to specifically destroy cancer cells. However, a significant fraction of tumors invariably relapses over time due to antigen loss, mutation or low cell surface density. Targeting multiple antigens simultaneously can in principle solve this problem, but that approach often fails with single chain variable fragments (scFvs) because of cross pairing and aggregation of CARs or the difficulty in assembling large antibody constructs. At the MD Anderson Nanobody Center we seek to overcome these and related hurdles by implementing single chain antibodies (nanobodies) in the development of novel immunotherapies. Through immunization of camelids (the source of natural nanobodies) and the creation of large human nanobody phage libraries we have developed a high-throughput program to rapidly isolate highly specific antibodies against tumor antigens. Our current projects include the production of multimeric CARs against cell surface as well as intracellular (peptide-HLA) targets in hematopoietic and solid tumors.
Education & Training
Degree-Granting Education
| 2002 | Rockefeller University, New York, NY, USA, PHD, Molecular Immunology |
| 1996 | Brigham Young University, Provo, UT, USA, BS, Molecular Biology |
Postgraduate Training
| 2002-2003 | Research Fellowship, Molecular Biology, California Institute of Technology, Pasadena, CA |
Experience & Service
Administrative Appointments/Responsibilities
Head, Regulome Project, National Institutes of Health, Bethesda, MD, 2010 - 2022
Senior Investigator, Department of Laboratory of Lymphocyte Nuclear Biology, National Institutes of Health, Bethesda, MD, 2004 - 2022
Honors & Awards
| 2021 | Salzman’s Virology Award, National Institutes of Health |
| 2014 | NIH Director’s Award, National Institutes of Health |
| 2010 | NIH Director’s Award, National Institutes of Health |
| 2010 | NIH MERIT Award, National Institutes of Health |
| 2008 | NIH MERIT Award, National Institutes of Health |
| 1996 | Brigham Young University Hypercube Scholar, Brigham Young University |
Selected Publications
Peer-Reviewed Articles
- Xu J, Xu K, Jung S, Conte A, Lieberman J, Muecksch F, Lorenzi JCC, Park S, Schmidt F, Wang Z, Huang Y, Luo Y, Nair MS, Wang P, Schulz JE, Tessarollo L, Bylund T, Chuang GY, Olia AS, Stephens T, Teng IT, Tsybovsky Y, Zhou T, Munster V, Ho DD, Hatziioannou T, Bieniasz PD, Nussenzweig MC, Kwong PD, Casellas R. Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants. Nature 595(7866):278-282, 2021. e-Pub 2021. PMID: 34098567.
- Wang Z, Schmidt F, Weisblum Y, Muecksch F, Barnes CO, Finkin S, Schaefer-Babajew D, Cipolla M, Gaebler C, Lieberman JA, Oliveira TY, Yang Z, Abernathy ME, Huey-Tubman KE, Hurley A, Turroja M, West KA, Gordon K, Millard KG, Ramos V, Da Silva J, Xu J, Colbert RA, Patel R, Dizon J, Unson-O'Brien C, Shimeliovich I, Gazumyan A, Caskey M, Bjorkman PJ, Casellas R, Hatziioannou T, Bieniasz PD, Nussenzweig MC. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature 592(7855):616-622, 2021. e-Pub 2021. PMID: 33567448.
- Dai HQ, Hu H, Lou J, Ye AY, Ba Z, Zhang X, Zhang Y, Zhao L, Yoon HS, Chapdelaine-Williams AM, Kyritsis N, Chen H, Johnson K, Lin S, Conte A, Casellas R, Lee CS, Alt FW. Loop extrusion mediates physiological Igh locus contraction for RAG scanning. Nature 590(7845):338-343, 2021. e-Pub 2021. PMID: 33442057.
- Ba Z, Lou J, Ye AY, Dai HQ, Dring EW, Lin SG, Jain S, Kyritsis N, Kieffer-Kwon KR, Casellas R, Alt FW. CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning. Nature 586(7828):305-310, 2020. e-Pub 2020. PMID: 32717742.
- Senigl F, Maman Y, Dinesh RK, Alinikula J, Seth RB, Pecnova L, Omer AD, Rao SSP, Weisz D, Buerstedde JM, Aiden EL, Casellas R, Hejnar J, Schatz DG. Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation. Cell Rep 29(12):3902-3915.e8, 2019. PMID: 31851922.
- Zhang X, Zhang Y, Ba Z, Kyritsis N, Casellas R, Alt FW. Fundamental roles of chromatin loop extrusion in antibody class switching. Nature 575(7782):385-389, 2019. e-Pub 2019. PMID: 31666703.
- El Khattabi L, Zhao H, Kalchschmidt J, Young N, Jung S, Van Blerkom P, Kieffer-Kwon P, Kieffer-Kwon KR, Park S, Wang X, Krebs J, Tripathi S, Sakabe N, Sobreira DR, Huang SC, Rao SSP, Pruett N, Chauss D, Sadler E, Lopez A, Nóbrega MA, Aiden EL, Asturias FJ, Casellas R. A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers. Cell 178(5):1145-1158.e20, 2019. e-Pub 2019. PMID: 31402173.
- Kouzine F, Wojtowicz D, Yamane A, Casellas R, Przytycka TM, Levens DL. In Vivo Chemical Probing for G-Quadruplex Formation. Methods Mol Biol 2035:369-382, 2019. PMID: 31444763.
- Delgado-Benito V. et al., Casellas R, Di Virgilio M. The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination. Mol Cell 72(4):636-649.e8, 2018. e-Pub 2018. PMID: 30293785.
- Pekowska A. et al., Casellas R, Huber W. Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency. Cell Syst 7(5):482-495.e10, 2018. e-Pub 2018. PMID: 30414923.
- Shastri N. et al., Casellas R, Brown EJ. Genome-wide Identification of Structure-Forming Repeats as Principal Sites of Fork Collapse upon ATR Inhibition. Mol Cell 72(2):222-238.e11, 2018. e-Pub 2018. PMID: 30293786.
- Vian L. et al., Casellas R. The Energetics and Physiological Impact of Cohesin Extrusion. Cell 173(5):1165-1178.e20, 2018. e-Pub 2018. PMID: 29706548.
- Li G. et al., Casellas R, Baltimore D. Epigenetic silencing of miR-125b is required for normal B-cell development. Blood 131(17):1920-1930, 2018. e-Pub 2018. PMID: 29555645.
- Gearhart PJ, Mock BA, Casellas R, Cancro MP. The Reign of Antibodies: A Celebration of and Tribute to Michael Potter and His Homogeneous Immunoglobulin Workshops. J Immunol 200(1):23-26, 2018. PMID: 29255086.
- Rao SSP. et al., Casellas R, Aiden EL. Cohesin Loss Eliminates All Loop Domains. Cell 171(2):305-320.e24, 2017. PMID: 28985562.
- Kieffer-Kwon KR. et al., Casellas R. Myc Regulates Chromatin Decompaction and Nuclear Architecture during B Cell Activation. Mol Cell 67(4):566-578.e10, 2017. e-Pub 2017. PMID: 28803781.
- Canela A. et al., Casellas R, Nussenzweig A. Genome Organization Drives Chromosome Fragility. Cell 170(3):507-521.e18, 2017. e-Pub 2017. PMID: 28735753.
- Kouzine F. et al., Casellas R, Levens D. Permanganate/S1 Nuclease Footprinting Reveals Non-B DNA Structures with Regulatory Potential across a Mammalian Genome. Cell Syst 4(3):344-356.e7, 2017. e-Pub 2017. PMID: 28237796.
- Wang Q. et al., Casellas R, Robbiani DF. The cell cycle restricts activation-induced cytidine deaminase activity to early G1. J Exp Med 214(1):49-58, 2017. e-Pub 2016. PMID: 27998928.
- Juan AH. et al., Casellas R, Zou J, Sartorelli V. Roles of H3K27me2 and H3K27me3 Examined during Fate Specification of Embryonic Stem Cells. Cell Rep 18(1):297, 2017. PMID: 28052258.
- Cruz AC. et al., Casellas R, Siegel RM. Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction. Nat Commun 7:13895, 2016. e-Pub 2016. PMID: 28008916.
- Zhang S. et al., Casellas R, Bustin M. HMGN proteins modulate chromatin regulatory sites and gene expression during activation of naïve B cells. Nucleic Acids Res 44(15):7144-58, 2016. e-Pub 2016. PMID: 27112571.
- Casellas R. et al.. Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity. Nat Rev Immunol 16(3):164-76, 2016. e-Pub 2016. PMID: 26898111.
- Teng G. et al., Casellas R, Schatz DG. RAG Represents a Widespread Threat to the Lymphocyte Genome. Cell 162(4):751-65, 2015. e-Pub 2015. PMID: 26234156.
- Aiden EL, Casellas R. Somatic Rearrangement in B Cells: It's (Mostly) Nuclear Physics. Cell 162(4):708-11, 2015. PMID: 26276627.
- Swaminathan S. et al., Casellas R, Müschen M. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nat Immunol 16(7):766-774, 2015. e-Pub 2015. PMID: 25985233.
- Pratama A. et al., Casellas R, Vinuesa CG. MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nat Commun 6:6436, 2015. e-Pub 2015. PMID: 25743066.
- Meng FL. et al., Casellas R, Alt FW. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell 159(7):1538-48, 2014. e-Pub 2014. PMID: 25483776.
- Qian J. et al., Casellas R. B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell 159(7):1524-37, 2014. e-Pub 2014. PMID: 25483777.
- Wang Q. et al., Casellas R, Robbiani DF. Epigenetic targeting of activation-induced cytidine deaminase. Proc Natl Acad Sci U S A 111(52):18667-72, 2014. e-Pub 2014. PMID: 25512519.
- Kouzine F. et al., Casellas R. Global regulation of promoter melting in naive lymphocytes. Cell 153(5):988-99, 2013. PMID: 23706737.
- Nakahashi H. et al., Casellas R. A genome-wide map of CTCF multivalency redefines the CTCF code. Cell Rep 3(5):1678-1689, 2013. e-Pub 2013. PMID: 23707059.
- Di Virgilio M. et al., Casellas R, Nussenzweig MC. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339(6120):711-5, 2013. e-Pub 2013. PMID: 23306439.
- Jankovic M, et al., Casellas R, Nussenzweig MC. 53BP1 alters the landscape of DNA rearrangements and suppresses AID-induced B cell lymphoma. Mol Cell 49(4):623-31, 2013. e-Pub 2013. PMID: 23290917.
- Bothmer A. et al., Casellas R, Robbiani DF. Mechanism of DNA resection during intrachromosomal recombination and immunoglobulin class switching. J Exp Med 210(1):115-23, 2013. e-Pub 2012. PMID: 23254285.
- Yamane A. et al., Casellas R. RPA accumulation during class switch recombination represents 5'-3' DNA-end resection during the S-G2/M phase of the cell cycle. Cell Rep 3(1):138-47, 2013. e-Pub 2013. PMID: 23291097.
- Barlow JH. et al., Casellas R, Nussenzweig A. Identification of early replicating fragile sites that contribute to genome instability. Cell 152(3):620-32, 2013. e-Pub 2013. PMID: 23352430.
- Nie Z. et al., Casellas R, Zhao K, Levens D. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151(1):68-79, 2012. PMID: 23021216.
- Baba M. et el., Casellas R. The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development. Blood 120(6):1254-61, 2012. e-Pub 2012. PMID: 22709692.
- Spehalski E. et al., Casellas R, Dunnick WA. Oncogenic Myc translocations are independent of chromosomal location and orientation of the immunoglobulin heavy chain locus. Proc Natl Acad Sci U S A 109(34):13728-32, 2012. e-Pub 2012. PMID: 22869734.
- Meredith MM. et al., Casellas R, Nussenzweig MC. Zinc finger transcription factor zDC is a negative regulator required to prevent activation of classical dendritic cells in the steady state. J Exp Med 209(9):1583-93, 2012. e-Pub 2012. PMID: 22851594.
- Kovalchuk AL. et al., Casellas R. Mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation. Proc Natl Acad Sci U S A 109(27):10972-7, 2012. e-Pub 2012. PMID: 22711821.
- Takahashi H. et al., Casellas R, O'Shea JJ. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat Immunol 13(6):587-95, 2012. e-Pub 2012. PMID: 22544395.
- Hakim O. et al., Casellas R. DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes. Nature 484(7392):69-74, 2012. e-Pub 2012. PMID: 22314321.
- Oliveira TY, Resch W, Jankovic M, Casellas R, Nussenzweig MC, Klein IA. Translocation capture sequencing: a method for high throughput mapping of chromosomal rearrangements. J Immunol Methods 375(1-2):176-81, 2012. e-Pub 2011. PMID: 22033343.
- Klein IA. et el., Casellas R, Nussenzweig MC. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 147(1):95-106, 2011. PMID: 21962510.
- Yamane A. et el., Casellas R. Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes. Nat Immunol 12(1):62-9, 2011. e-Pub 2010. PMID: 21113164.
- Pavri R. et el., Casellas R, Nussenzweig MC. Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5. Cell 143(1):122-33, 2010. PMID: 20887897.
- Daniel JA. et al., Casellas R, Nussenzweig A. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science 329(5994):917-23, 2010. e-Pub 2010. PMID: 20671152.
- Aiba Y. et al., Casellas R, Kurosaki T. Preferential localization of IgG memory B cells adjacent to contracted germinal centers. Proc Natl Acad Sci U S A 107(27):12192-7, 2010. e-Pub 2010. PMID: 20547847.
- Takizawa M. et el., Casellas R, Janz S. Genetic reporter system for oncogenic Igh-Myc translocations in mice. Oncogene 29(28):4113-20, 2010. e-Pub 2010. PMID: 20453890.
- Kuchen S. et el., Casellas R. Regulation of microRNA expression and abundance during lymphopoiesis. Immunity 32(6):828-39, 2010. e-Pub 2010. PMID: 20605486.
- Ji Y. et el. Casellas R, Schatz DG. The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci. Cell 141(3):419-31, 2010. e-Pub 2010. PMID: 20398922.
- Klemm L. et el. Casellas R, Müschen M. The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia. Cancer Cell 16(3):232-45, 2009. PMID: 19732723.
- Casellas R, Yamane A, Kovalchuk AL, Potter M. Restricting activation-induced cytidine deaminase tumorigenic activity in B lymphocytes. Immunology 126(3):316-28, 2009. PMID: 19302140.
- Takizawa M. et al, Casellas R. AID expression levels determine the extent of cMyc oncogenic translocations and the incidence of B cell tumor development. J Exp Med 205(9):1949-57, 2008. e-Pub 2008. PMID: 18678733.
- Teng G, et al. Casellas R, Papavasiliou FN. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 28(5):621-9, 2008. e-Pub 2008. PMID: 18450484.
- Kruhlak M, et al. Casellas R. The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks. Nature 447(7145):730-4, 2007. PMID: 17554310.
- Crouch EE, et al. Casellas R. Regulation of AID expression in the immune response. J Exp Med 204(5):1145-56, 2007. e-Pub 2007. PMID: 17452520.
- Casellas R, et al.. Igkappa allelic inclusion is a consequence of receptor editing. J Exp Med 204(1):153-60, 2007. e-Pub 2007. PMID: 17210730.
- Furumoto Y. et al. Casellas R, Rivera J. Cutting Edge: Lentiviral short hairpin RNA silencing of PTEN in human mast cells reveals constitutive signals that promote cytokine secretion and cell survival. J Immunol 176(9):5167-71, 2006. PMID: 16621980.
- Casellas R. et al.. OcaB is required for normal transcription and V(D)J recombination of a subset of immunoglobulin kappa genes. Cell 110(5):575-85, 2002. PMID: 12230975.
- Petersen S, Casellas R,. et al.. AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching. Nature 414(6864):660-665, 2001. PMID: 11740565.
- Casellas R. et al. Contribution of receptor editing to the antibody repertoire. Science 291(5508):1541-4, 2001. PMID: 11222858.
- Meffre E, Casellas R, Nussenzweig MC. Antibody regulation of B cell development. Nat Immunol 1(5):379-85, 2000. PMID: 11062496.
- Yu W, et al. Casellas R, Nussenzweig MC. RAG expression in B cells in secondary lymphoid tissues. Cold Spring Harb Symp Quant Biol 64:207-10, 1999. PMID: 11232286.
- Casellas R, Brivanlou AH. Xenopus Smad7 inhibits both the activin and BMP pathways and acts as a neural inducer. Dev Biol 198(1):1-12, 1998. PMID: 9640328.
- Casellas R, et al. Ku80 is required for immunoglobulin isotype switching. EMBO J 17(8):2404-11, 1998. PMID: 9545251.
- Papavasiliou F, Casellas R. et al. V(D)J recombination in mature B cells: a mechanism for altering antibody responses. Science 278(5336):298-301, 1997. PMID: 9323210.
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CV information above last modified April 29, 2024