+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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

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

Proceedings of the National Academy of Sciences of the United States of America 107(17): 7869-7874

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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 052269067

Download citation: RISBibTeXText

PMID: 20385820

DOI: 10.1073/pnas.1003525107

Related references

Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage. Proceedings of the National Academy of Sciences of the United States of America 106(2): 552-557, 2009

Combined heterozygous loss of Ebf1 and Pax5 allows for T-lineage conversion of B cell progenitors. Journal of Experimental Medicine 212(7): 1109-1123, 2015

Role of Runx1 in adult hematopoiesis Analysis of Runx1-GFP knock-in mice reveals differential lineage expression. Blood 102(11): 131a, November 16, 2003

Role of RUNX1 in adult hematopoiesis: analysis of RUNX1-IRES-GFP knock-in mice reveals differential lineage expression. Blood 103(7): 2522-2529, 2003

Runx1-Cbfβ facilitates early B lymphocyte development by regulating expression of Ebf1. Journal of Experimental Medicine 209(7): 1255-1262, 2012

Expression of estrogenicity genes in a lineage cell culture model of human breast cancer progression. Breast Cancer Research and Treatment 120(1): 35-45, 2010

A dose-dependent role for EBF1 in repressing non-B-cell-specific genes. European Journal of Immunology 41(6): 1787-1793, 2011

Single Cell Marking and Cell Lineage in Animal Development || Segments, Lineage Boundaries and the Domains of Expression of Homeotic Genes. Philosophical Transactions of the Royal Society of London Series B Biological Sciences 312(1153): 179-187, 1985

RUNX1 repression-independent mechanisms of leukemogenesis by fusion genes CBFB-MYH11 and AML1-ETO (RUNX1-RUNX1T1). Journal of Cellular Biochemistry 110(5): 1039-1045, 2010

Near-triploidy and near-tetraploidy in childhood acute lymphoblastic leukemia: association with B-lineage blast cells carrying the ETV6-RUNX1 fusion, T-lineage immunophenotype, and favorable outcome. Cancer Genetics and Cytogenetics 169(1): 50-57, 2006

EBNA2 Drives Formation of New Chromosome Binding Sites and Target Genes for B-Cell Master Regulatory Transcription Factors RBP-jκ and EBF1. Plos Pathogens 12(1): E1005339-E1005339, 2016

Cigarette tar phenols impede T cell cycle progression by inhibiting cyclin-dependent kinases. Molecular Immunology 44(4): 488-493, 2006

Cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion in a case of progressive chronic myeloid leukemia: a complex chromosomal rearrangement of underestimated frequency in disease progression?. Genes, Chromosomes & Cancer 47(12): 1110-1117, 2008

EBF1 is essential for B-lineage priming and establishment of a transcription factor network in common lymphoid progenitors. Journal of Immunology 181(5): 3364-3372, 2008

Haploinsufficiencies of FOXF1 and FOXC2 genes associated with lethal alveolar capillary dysplasia and congenital heart disease. American Journal of Medical Genetics. Part A 152a(5): 1257-1262, 2010