Therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) are late complications of cytotoxic therapy of both malignant and non-malignant diseases. Characteristic recurring abnormalities of chromosomes 5 and/or 7 are frequently noted in t-MDS/t-AML. In the University of Chicago series of 306 patients with t-MDS/t-AML, we observed loss of 5q or 7q in 214 (70%) patients examined. In previous studies, we defined a 970 kb commonly deleted segment (CDS) within 5q31 flanked by D5S479 and D5S500. In subsequent studies, we generated a complete transcript map of this CDS, and identified and cloned 20 genes. Our mutation analysis of all candidate genes within the CDS of 5q has not revealed inactivating mutations in the remaining alleles, nor is there evidence of transcriptional silencing via DMA methylation, observations that are compatible with a haploinsufficiency model. By using mouse models, we have determined that EGR1, a candidate tumor suppressor gene (TSG) within the CDS of 5q, acts by haploinsufficiency and cooperates with mutations induced by alkylating agents to induce myeloid leukemias. Moreover, EGR1, which encodes a transcription factor, is involved in murine stress erythropoiesis. We hypothesize that 5q31 contains one or more myeloid TSGs that act by haploinsufficiency.
In Aim 1, we will examine the role of Egr1 in hematopoiesis and leukemogenesis in our mouse model by identifying mutations that cooperate with Egr1 in the pathogenesis of myeloid disorders, and interrogating human t- AMLs for mutations of the genes identified.
In Aim 2, we will evaluate whether loss of multiple genes within the CDS of 5q plays a role in leukemogenesis by generating conditional and germline mice with a deletion of the region syntenic to the CDS, and we will use mice with heterozygous and homozygous deletions to identify candidate genes within the CDS, as well as other genes that cooperate with the deletion in leukemogenesis.
In Aim 3, we will refine the smallest CDS of 7q22, and define additional deleted segments of 7q by using cytogenetic mapping techniques and molecular analysis of copy number changes to examine leukemias with deletions or translocations of 7q (collaboration with Projects 2 and 4). The identification of myeloid leukemia genes from the CDSs of 5q and 7q represent a high experimental priority due to the high frequency of these abnormalities, and the poor outcome associated with these abnormalities, as well as the ramifications toward identifying individuals at risk for the development of t-AML, and in the selection of the appropriate therapy for treatment of the primary malignant disease. Finally, understanding the biochemical functions of the encoded proteins may provide insights into myelopoiesis and leukemic transformation, and may ultimately lead to the development of rational new therapeutics.
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