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Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):E2039-46. doi: 10.1073/pnas.1600557113. Epub 2016 Mar 18.

Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2.

Author information

1
Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, United Kingdom.
2
Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
3
Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; lstaudt@mail.nih.gov.

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.

KEYWORDS:

cancer biology; germinal center; lymphoma

PMID:
26993806
PMCID:
PMC4833274
DOI:
10.1073/pnas.1600557113
[Indexed for MEDLINE]
Free PMC Article

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