Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders

• Published in: Blood Vol. 110; no. 2; pp. 719 - 726
• Main Authors: Joslin, John M., Fernald, Anthony A., Tennant, Thelma R., Davis, Elizabeth M., Kogan, Scott C., Anastasi, John, Crispino, John D., Le Beau, Michelle M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.07.2007; American Society of Hematology
• Series: Neoplasia
• Subjects: Animals; Bone Marrow Cells - pathology; Cell Differentiation; Chromosome Mapping; Chromosomes, Human, Pair 5; Early Growth Response Protein 1 - deficiency; Early Growth Response Protein 1 - genetics; Humans; Leukemia, Myeloid - genetics; Mice; Mice, Knockout; Mutagenesis; Myelodysplastic Syndromes - genetics; Neoplasia; Polymorphism, Single-Stranded Conformational; Sequence Deletion; Stem Cells - pathology; Stem Cells - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-01-068809

Loss of a whole chromosome 5 or a deletion of the long arm, del(5q), is a recurring abnormality in myelodysplastic syndromes (MDSs) 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 increased rates and with shorter latencies 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 suggest that haploinsufficiency for Egr1 plays a role in murine leukemogenesis, and in the development of AML/MDS characterized by abnormalities of chromosome 5.