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Blood, 15 July 2007, Vol. 110, No. 2, pp. 719-726.
Prepublished online as a Blood First Edition Paper on April 9, 2007; DOI 10.1182/blood-2007-01-068809.
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Submitted January 17, 2007
Accepted March 21, 2007
Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders
John M Joslin, Anthony A Fernald, Thelma R Tennant, Elizabeth M. Davis, Scott C Kogan, John Anastasi, John D Crispino, and Michelle M. Le Beau*
Section of Hematology/Oncology & the Cancer Research Center, University of Chicago, Chicago, Illinois, United States
Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California, United States
Department of Pathology, University of Chicago, Chicago, Illinois, United States
Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States
* Corresponding author; email: mlebeau{at}medicine.bsd.uchicago.edu.
Loss of a whole chromosome 5 or a deletion of the long arm, del(5q), is a recurring abnormality in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). To identify a leukemia-related gene on chromosome 5, we previously delineated a 970 kb segment of 5q31 that is deleted in all patients examined, and prepared a transcript map of this region. EGR1 is a candidate tumor suppressor gene within the commonly deleted segment of 5q, and encodes a zinc finger transcription factor. To test the hypothesis that loss of function of Egr1 is an initiating event in the pathogenesis of AML/MDS, Egr1-deficient mice were treated with a potent DNA alkylating agent, N-ethyl-Nitrosourea (ENU), to induce secondary cooperating mutations. Egr1+/- and Egr1-/- mice treated with ENU developed immature T-cell lymphomas (CD4+,CD8+) or a myeloproliferative disorder (MPD) at an increased rate and shorter latency than that of wild-type littermates. The MPD was characterized by an elevated white blood cell count, anemia, and thrombocytopenia with ineffective erythropoiesis. Biallelic mutations of Egr1 were not observed in MPDs in Egr1+/- mice. Our data suggests that haploinsufficiency for Egr1 plays a role in murine leukemogenesis, and in the development of AML/MDS characterized by abnormalities of chromosome 5.
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