title: Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders.
abstract: 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.
authors.affiliation: Section of Hematology/Oncology and the Cancer Research Center, University of Chicago, IL 60637, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Joslin
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Fernald
authors.forename: Thelma R
authors.initials: TR
authors.lastname: Tennant
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Davis
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: John
authors.initials: J
authors.lastname: Anastasi
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D017384:Sequence Deletion; D013234:Stem Cells / Q000473:pathology / Q000502:physiology
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse