title: Pre-B cell receptor-mediated activation of BCL6 induces pre-B cell quiescence through transcriptional repression of MYC.
abstract: Initial cell surface expression of the pre-B cell receptor induces proliferation. After 2 to 5 divisions, however, large pre-BII (Fraction C') cells exit cell cycle to become resting, small pre-BII cells (Fraction D). The mechanism by which pre-BII cells exit cell cycle, however, is currently unclear. The checkpoint at the Fraction C'-D transition is critical for immunoglobulin light chain gene recombination and to prevent malignant transformation into acute lymphoblastic leukemia. Here we demonstrate that inducible activation of pre-B cell receptor signaling induces cell-cycle exit through up-regulation of the transcriptional repressor BCL6. Inducible activation of BCL6 downstream of the pre-B cell receptor results in transcriptional repression of MYC and CCND2. Hence, pre-B cell receptor-mediated activation of BCL6 limits pre-B cell proliferation and induces cellular quiescence at the small pre-BII (Fraction D) stage.
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Nahar
authors.forename: Parham
authors.initials: P
authors.lastname: Ramezani-Rad
authors.forename: Maximilian
authors.initials: M
authors.lastname: Mossner
authors.forename: Cihangir
authors.initials: C
authors.lastname: Duy
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.forename: Sinisa
authors.initials: S
authors.lastname: Dovat
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.forename: B Hilda
authors.initials: BH
authors.lastname: Ye
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000502:physiology; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054420:Pre-B Cell Receptors / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C490010:Bcl6 protein, mouse; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D004268:DNA-Binding Proteins; D007147:Immunoglobulin Light Chains; C489428:Myc protein, mouse; D054420:Pre-B Cell Receptors; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc