title: Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2.
abstract: The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B. Genome-wide chromatin immunoprecipitation (ChIP) analysis and gene-expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL-10, ELL2, XBP1, MYC, TERT, and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies and a recurrent mutation of threonine 223 in the DNA-binding domain of OCT2. This neomorphic mutation subtly alters the DNA-binding preference of OCT2, leading to the transactivation of noncanonical target genes including HIF1a and FCRL3 Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface, we reveal a requirement for this protein-protein interface that ultimately might be exploited therapeutically. Our findings, combined with the predominantly B-cell-restricted expression of OCT2 and the absence of a systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL while avoiding systemic toxicity.
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: George W
authors.initials: GW
authors.lastname: Wright
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: James D
authors.initials: JD
authors.lastname: Phelan
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Webster
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Lixin
authors.initials: L
authors.lastname: Rui
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Holger
authors.initials: H
authors.lastname: Kohlhammer
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Masao
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; lstaudt@mail.nih.gov.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000502:physiology*; D000075102:Organic Cation Transporter 2
chemical_list: D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491012:Slc22a2 protein, mouse
keywords: cancer biology; germinal center; lymphoma