TY - JOUR
T1 - Early B-cell factor-associated zinc-finger gene is a frequent target of retroviral integration in murine B-cell lymphomas
AU - Warming, Søren
AU - Suzuki, Takeshi
AU - Yamaguchi, Terry P.
AU - Jenkins, Nancy A.
AU - Copeland, Neal G.
N1 - Funding Information:
We thank Kristin Biris for help with in situ hybridization and Linda Cleveland for DNA sequencing. We also thank James Cherry, Kelly Martin, Casey Frankenberger and David Munroe from the Gene Expression Laboratory, NCI-Frederick, for help with the real-time RT–PCR. This research was supported by the National Cancer Institute, US Department of Health and Human Services (NAJ, TPY and NGC) and the Danish Natural Science Research Council (SW).
PY - 2004/4/8
Y1 - 2004/4/8
N2 - The early B-cell factor (EBF)-associated zinc-finger protein (EBFAZ) binds to and negatively regulates EBF, a basic helix-loop-helix transcription factor required for B-cell lineage commitment and development of the olfactory epithelium. It also binds to SMA- and MAD-related protein 1 (SMAD1) and SMAD4 in response to bone morphogenic protein 2 (BMP2) signaling. It is highly related to ecotropic viral integration site 3 (EVI3), a protein that, like EBFAZ, contains 30 Krüppel-like zinc-finger repeats. In previous studies, we showed that Evi3 is a frequent target of retroviral integration in AKXD27 B-cell lymphomas. Here, we show that EBFAZ is also a frequent target. Integrations at Ebfaz and Evi3 are mutually exclusive, suggesting that they function in the same tumor pathway. Lymphomas with integrations at Ebfaz or Evi3 express the pre-B-cell-specific marker immunoglobulin lambda chain 5, and contain immunoglobulin heavy-chain rearrangements, suggesting that they are blocked at an early B-cell stage. Unlike Evi3, which is expressed at low levels in normal B cells, or Ebfaz, which is not expressed in B cells, both genes are highly expressed following viral integration. Collectively, our results suggest that ectopic expression of Ebfaz can substitute for the upregulated expression of Evi3 in B-cell disease and highlight the importance of this gene family in hematopoietic cancer.
AB - The early B-cell factor (EBF)-associated zinc-finger protein (EBFAZ) binds to and negatively regulates EBF, a basic helix-loop-helix transcription factor required for B-cell lineage commitment and development of the olfactory epithelium. It also binds to SMA- and MAD-related protein 1 (SMAD1) and SMAD4 in response to bone morphogenic protein 2 (BMP2) signaling. It is highly related to ecotropic viral integration site 3 (EVI3), a protein that, like EBFAZ, contains 30 Krüppel-like zinc-finger repeats. In previous studies, we showed that Evi3 is a frequent target of retroviral integration in AKXD27 B-cell lymphomas. Here, we show that EBFAZ is also a frequent target. Integrations at Ebfaz and Evi3 are mutually exclusive, suggesting that they function in the same tumor pathway. Lymphomas with integrations at Ebfaz or Evi3 express the pre-B-cell-specific marker immunoglobulin lambda chain 5, and contain immunoglobulin heavy-chain rearrangements, suggesting that they are blocked at an early B-cell stage. Unlike Evi3, which is expressed at low levels in normal B cells, or Ebfaz, which is not expressed in B cells, both genes are highly expressed following viral integration. Collectively, our results suggest that ectopic expression of Ebfaz can substitute for the upregulated expression of Evi3 in B-cell disease and highlight the importance of this gene family in hematopoietic cancer.
KW - B-cell lymphoma
KW - EBFAZ
KW - EVI3
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U2 - 10.1038/sj.onc.1207452
DO - 10.1038/sj.onc.1207452
M3 - Article
C2 - 15048087
AN - SCOPUS:2342473288
SN - 0950-9232
VL - 23
SP - 2727
EP - 2731
JO - Oncogene
JF - Oncogene
IS - 15
ER -