Molecular Characterization of Distinct Hot Spot Regions on Chromosome 7q in Myeloid Leukemias.

Abstract In recent years several groups initiated the molecular characterization of deletion and translocation breakpoints affecting the long arm of chromosome 7 (7q−) to identify genes that are involved in the pathogenesis of myeloid leukemias. Based on these studies a commonly deleted segment (CDS) of approximately 2 Mb in size was identified in chromosomal band 7q22 flanked by the microsatellite markers D7S1503 and D7S1841. Recently, the MLL5 gene (mixed lineage leukemia 5) has been cloned and mapped to the CDS as an interesting candidate gene for chromosome 7q associated leukemias. However, the pathogenic role of MLL5 in myeloid leukemias has not been demonstrated yet. In addition, for the less frequent deletion/translocation breakpoints affecting the distal part of chromosome 7q a 4 to 5 Mb sized CDS was defined encompassing chromosomal bands 7q35 to q36. The heterogeneity of deletion/translocation breakpoints on 7q suggests the existence of more than one disease-related gene. We aimed to identify and characterize translocation and deletion breakpoints in a large series of myeloid leukemias with chromosome 7q aberrations using fluorescence in situ hybridisation (FISH) and array-based comparative genomic hybridization (array CGH). Once, novel hot spot regions were identified, transcriptional map(s) were constructed allowing the identification of candidate genes, expressed sequences or miR-sites. FISH with a physical map of well defined YAC/BAC/PAC clones covering the long arm of chromosome 7 was performed on a series of 105 myeloid leukemias [acute myeloid leukaemia, (AML); myelodysplastic syndrome (MDS); myeloproliferative disorders, (MPD)] exhibiting chromosome 7q aberrations on banding analysis. Selected patients were analysed by array CGH and results were confirmed by hybridisation of the corresponding DNA clones. Transcriptional map(s) were constructed using public databases. While most of the deletions were large encompassing the previously published CDS, we identified a distinct 2 Mb sized CDS in the proximal part of 7q22 that was defined by five patients all exhibiting small deletions. This segment contains several candidate genes including the putative tumor-suppressor genes CUTL1, RASA4, EPO and FBXL13. Interestingly, this CDS is located close to multiple miR-sites, which usually indicate common fragile sites in the human genome. In chromosomal bands 7q35–q36 we localized the breakpoint of an unbalanced translocation from a patient with secondary AML between the markers D7S1925 and D7S1395. This region was recently characterized as a common fragile site in the human genome, named FRA7I. Furthermore, the translocation breakpoint t(3;7)(p13;q35) of a second patient with therapy-related AML was cloned into a 100 kb sized genomic segment located centromeric the CNTNAP2-gene close to the proximal border of the CDS. Our data further indicate the remarkable heterogeneity of deletion and translocation breakpoints on 7q supporting the hypothesis of multiple genes involved in 7q-associated myeloid leukemias. Using techniques such as FISH and array CGH known CDS as well as novel hot spot regions were identified. Transcriptional maps from those regions may serve as important starting points for the identification of pathogenetically relevant genes.

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