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Compound haploinsufficiencies of Ebf1 and Runx1 genes impede B cell lineage progression

Academic Article
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Overview

authors

  • Lukin, K.
  • Fields, S.
  • Lopez, D.
  • Cherrier, M.
  • Ternyak, K.
  • Ramirez, J.
  • Feeney, Ann
  • Hagman, J.

publication date

  • April 2010

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated the synergistic activation of Cd79a (mb-1) genes by EBF1 and its functional partner, RUNX1. Here, we identified consequences of Ebf1 haploinsufficiency together with haploinsufficiency of Runx1 genes in mice. Although numbers of "committed" pro-B cells were maintained in Ebf1(+/-)Runx1(+/-) (ER(het)) mice, activation of B cell-specific gene transcription was depressed in these cells. Expression of genes encoding Aiolos, kappa0 sterile transcripts, CD2 and CD25 were reduced and delayed in ER(het) pro-B cells, whereas surface expression of BP-1 was increased on late pro-B cells in ER(het) mice. Late pre-B and immature and mature B cells were decreased in the bone marrow of Ebf1(+/-) (E(het)) mice and were nearly absent in ER(het) mice. Although we did not observe significant effects of haploinsuficiencies on IgH or Igkappa rearrangements, a relative lack of Iglambda rearrangements was detected in E(het) and ER(het) pre-B cells. Together, these observations suggest that B cell lineage progression is impaired at multiple stages in the bone marrow of E(het) and ER(het) mice. Furthermore, enforced expression of EBF1 and RUNX1 in terminally differentiated plasmacytoma cells activated multiple early B cell-specific genes synergistically. Collectively, these studies illuminate the effects of reduced Ebf1 dosage and the compounding effects of reduced Runx1 dosage. Our data confirm and extend the importance of EBF1 in regulating target genes and Ig gene rearrangements necessary for B cell lineage specification, developmental progression, and homeostasis.

subject areas

  • Animals
  • Antigens, CD2
  • B-Lymphocytes
  • Cell Differentiation
  • Cell Lineage
  • Core Binding Factor Alpha 2 Subunit
  • DNA Primers
  • Flow Cytometry
  • Gene Dosage
  • Gene Expression Regulation, Developmental
  • Interleukin-2 Receptor alpha Subunit
  • Mice
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators
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Research

keywords

  • B cell development
  • B lymphopoiesis
  • immunoglobulin gene rearrangements
  • transcription factor dosage
  • transcriptional networks
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Identity

PubMed Central ID

  • PMC2867885

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1003525107

PubMed ID

  • 20385820
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Additional Document Info

start page

  • 7869

end page

  • 7874

volume

  • 107

issue

  • 17

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