Rna Sequencing Reveals Cux1 To Be A Conserved Tumor Suppressor In Acute Myeloid Leukemia Associated With Loss Or Deletion Of Chromosome 7

Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in acute myeloid leukemia (AML), occurring in 9% of de novo AML and 50% of therapy-related myeloid neoplasms (t-MN). Abnormalities of chromosome 7 carry an adverse prognosis. Despite intensive analysis by many laboratories, and the identification of multiple minimally deleted regions on 7q, the putative tumor suppressor(s) on chromosome 7 is currently unknown. We performed transcriptome sequencing on 22 samples and SNP array analysis on 35 samples from patients with myeloid neoplasms, half of which contain -7/del(7q). Copy number analysis identified a 2.17 Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor normally expressed highly in hematopoietic stem cells. CUX1 was found to be disrupted in a translocation resulting in a chimeric RNA fusion transcript in one patient. We found the CUX1 transcript and protein to be expressed at haploinsufficent levels in -7/del(7q) leukemias. To test the tumor suppressor activity of CUX1, the drosophila homologue, CUT, was knocked-down in Drosophila melanogaster hemocytes, which led to significantly increased numbers of hemocytes and melanotic tumor formation. Restoration of CUX1 expression in a human AML cell line with -7 decreased proliferation. These data indicate that CUX1 is a conserved, haploinsufficient, tumor suppressor that promotes leukemogenesis in -7/del(7q) AML. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-411. doi:1538-7445.AM2012-LB-411