title: Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies.
abstract: Although numerous mouse models of B-cell malignancy have been developed via the enforced expression of defined oncogenic lesions, the feasibility of generating lineage-defined human B-cell malignancies using mice reconstituted with modified human hematopoietic stem cells (HSCs) remains unclear. In fact, whether human cells can be transformed as readily as murine cells by simple oncogene combinations is a subject of considerable debate. Here, we describe the development of humanized mouse model of MYC/BCL2-driven 'double-hit' lymphoma. By engrafting human HSCs transduced with the oncogene combination into immunodeficient mice, we generate a fatal B malignancy with complete penetrance. This humanized-MYC/BCL2-model (hMB) accurately recapitulates the histopathological and clinical aspects of steroid-, chemotherapy- and rituximab-resistant human 'double-hit' lymphomas that involve the MYC and BCL2 loci. Notably, this model can serve as a platform for the evaluation of antibody-based therapeutics. As a proof of principle, we used this model to show that the anti-CD52 antibody alemtuzumab effectively eliminates lymphoma cells from the spleen, liver and peripheral blood, but not from the brain. The hMB humanized mouse model underscores the synergy of MYC and BCL2 in 'double-hit' lymphomas in human patients. Additionally, our findings highlight the utility of humanized mouse models in interrogating therapeutic approaches, particularly human-specific monoclonal antibodies.
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Leskov
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Department I of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne, Germany.|Cluster of Excellence for Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Pallasch
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Drake
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Bettina P
authors.initials: BP
authors.lastname: Iliopoulou
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Souza
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Ching-Hung
authors.initials: CH
authors.lastname: Shen
authors.affiliation: Department I of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne, Germany.|Department of Hematopathology, UT M.D. Anderson Cancer Center Houston, TX 77030, USA.
authors.forename: Carmen D
authors.initials: CD
authors.lastname: Schweighofer
authors.affiliation: Cluster of Excellence for Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Lynne
authors.initials: L
authors.lastname: Abruzzo
authors.affiliation: Department I of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne, Germany.|Cluster of Excellence for Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Lukas P
authors.initials: LP
authors.lastname: Frenzel
authors.affiliation: Department I of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne, Germany.|Cluster of Excellence for Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Clemens M
authors.initials: CM
authors.lastname: Wendtner
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hemann
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D019683:Penetrance; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc