title: Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells.
abstract: Mantle cell lymphoma (MCL) is a highly aggressive B-cell lymphoma resistant to conventional chemotherapy. Although defined by the characteristic t(11;14) translocation, MCL has not been recapitulated in transgenic mouse models of cyclin D1 overexpression alone. Indeed, several genetic aberrations have been identified in MCL that may contribute to its pathogenesis and chemoresistance. Of particular interest is the frequent biallelic deletion of the proapoptotic BCL-2 family protein BIM. BIM exerts its pro-death function via its α-helical BH3 death domain that has the dual capacity to inhibit antiapoptotic proteins such as BCL-2 and MCL-1 and directly trigger proapoptotic proteins such as the mitochondrial executioner protein BAX. To evaluate a functional role for Bim deletion in the pathogenesis of MCL, we generated cyclin D1-transgenic mice harboring Bim-deficient B cells. In response to immunization, Eμ(CycD1)CD19(CRE)Bim(fl/fl) mice manifested selective expansion of their splenic mantle zone compartment. Three distinct immune stimulation regimens induced lymphomas with histopathologic and molecular features of human MCL in a subset of mice. Thus, deletion of Bim in B cells, in the context of cyclin D1 overexpression, disrupts a critical control point in lymphoid maturation and predisposes to the development of MCL. This genetic proof of concept for MCL pathogenesis suggests an opportunity to reactivate the death pathway by pharmacologic mimicry of proapoptotic BIM.
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Katz
authors.forename: James L
authors.initials: JL
authors.lastname: Labelle
authors.forename: Hailong
authors.initials: H
authors.lastname: Meng
authors.forename: Regina P
authors.initials: RP
authors.lastname: Valeriano
authors.forename: Jill K
authors.initials: JK
authors.lastname: Fisher
authors.forename: Heather
authors.initials: H
authors.lastname: Sun
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D000072224:Bcl-2-Like Protein 11; D002453:Cell Cycle; D019938:Cyclin D1 / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D016130:Immunophenotyping; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C530105:Ccnd1 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1