TY - JOUR
T1 - Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders
AU - Joslin, John M.
AU - Fernald, Anthony A.
AU - Tennant, Thelma R.
AU - Davis, Elizabeth M.
AU - Kogan, Scott C.
AU - Anastasi, John
AU - Crispino, John D.
AU - Le Beau, Michelle M.
PY - 2007/7/15
Y1 - 2007/7/15
N2 - 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 litter-mates. 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.
AB - 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 litter-mates. 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.
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U2 - 10.1182/blood-2007-01-068809
DO - 10.1182/blood-2007-01-068809
M3 - Article
C2 - 17420284
AN - SCOPUS:34547092452
SN - 0006-4971
VL - 110
SP - 719
EP - 726
JO - Blood
JF - Blood
IS - 2
ER -