Loss of Egr1 plays a role in murine leukemogenesis and may play a role in the development of acute myeloid leukemia and therapy-related acute myeloid leukemia.

摘要

Loss of a whole chromosome 5 or del(5q), is observed in 10% of patients with a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) arising de novo, and in 40% of patients with therapy-related MDS or AML (t-MDS/t-AML). In previous studies, our laboratory identified a commonly deleted segement (CDS) of chromosome 5. Mutation analysis of 20 candidate genes within the CDS did not reveal inactivating mutations in the remaining alleles, nor was there evidence of transcriptional silencing via DNA methylation. These observations are compatible with a haploinsufficiency model in which loss of one allele of the relevant gene(s) perturbs cell fate.{09}One candidate gene is EGR1, which encodes a zinc finger transcription factor that is a member of the WT1 family of transcription factors. EGR1 has been shown to regulate hematopoietic cytokine levels and play a role in controlling proliferation, growth arrest, differentiation, and apoptosis. Loss of Egr1 function may allow hematopoietic stem cells to bypass Tp53-mediated senescence or apoptosis, thereby contributing to leukemogenesis. We evaluated the role of Egr1 in hematopoiesis using Egr1-deficient mice. The Egr1-/- mice display elevated white blood cell counts, elevated lymphocytes, and decreased neutrophil counts. Egr1-null mice have elevated serum Epo levels and display increased signaling through EpoR. Egr1 -deficient mice treated with N-nitroso-N-ethylurea (ENU), a potent DNA alkylating agent, develop MPD or T cell lymphoma. Egr1-deficient mice developed MPD or lymphoma at an increased frequency compared to wild-type animals, indicating that Egr1 cooperates with other mutations in the pathogenesis of hematopoietic neoplasms. MPD is characterized by elevated white blood cell counts, anemia, and thrombocytopenia, with ineffective erythropoiesis in the bone marrow and spleen. To examine the role of Egr1 in erythropoiesis, we evaluated the erythropoiesic response to acute hemolytic anemia by treating Egr-l-deficient mice with phenylhydrazine. Following PHZ treatment Egr1-null mice become anemic, consistent with an iron deficiency. Egr1-null mice have decreased levels of serum iron following PHZ treatment, and have reduced Hmox1 (heme oxygenase1) expression in splenic macrophages. Together, these results suggest a role for Egr1 in murine erythropoiesis and in the development of myeloid leukemias characterized by abnormalities of chromosome 5.