Molecular Cytogenetic Characterization of a Critical Region in Bands 7q35-q36 Commonly Deleted in Malignant Myeloid Disorders

Abstract

Loss of chromosome 7 (−7) or deletion of the long arm (7q−) are recurring chromosome abnormalities in myeloid leukemias. The association of −7/7q− with myeloid leukemia suggests that these regions contain novel tumor suppressor gene(s), whose loss of function contribute to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified, one in band q22 and another in bands q32-q35. Presently there are no data available on the molecular delineation of the distal critical region. In this study we analyzed bone marrow and blood samples from 13 patients with myeloid leukemia (de novo myelodysplastic syndrome [MDS] , n = 3; de novo acute myeloid leukemia [AML], n = 9; therapy-related (t-) AML, n = 1) which, on chromosome banding analysis, exhibited deletions (n = 12) or in one case a balanced translocation involving bands 7q31-qter using fluorescence in situ hybridization (FISH). As probes we used representative clones from a contig map of yeast artificial chromosome (YAC) clones that spans chromosome bands 7q31.1-qter. In the 12 cases with loss of 7q material, we identified a commonly deleted region of approximately 4 to 5 megabasepairs in size encompassing the distal part of 7q35 and the proximal part of 7q36. Furthermore, the breakpoint of the reciprocal translocation from the patient with t-AML was localized to a 1,300-kb sized YAC clone that maps to the proximal boundary of the commonly deleted region. Interestingly, in this case both homologs of chromosome 7 were affected: one was lost (−7) and the second exhibited the t(7q35). The identification and delineation of translocation and deletion breakpoints provides the first step toward the identification of the gene(s) involved in the pathogenesis of 7q35-q36 aberrations in myeloid disorders.

Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells

“…Moreover, the robustness of our cellular MDS phenotypes could provide a platform for phenotype-driven drug screens to identify small molecules that ameliorate these phenotypes. Our 20 Mb region coincides with some proposed commonly deleted regions from patient studies, but not with others 38 , 9 , 39 . Among other candidate haploinsufficient genes on chr7q, MLL3 ref 40 is located inside our critical region, but it was not found differentially expressed between del(7q)- and isogenic normal iPSCs in our analysis and therefore not included in our library screen ( Supplementary Table 7 ).…”

Genetic profiling in acute myeloid leukaemia ─ where are we and what is its role in patient management

“…EZH2 is involved in many other myeloid malignancies and may act as a tumour suppressor gene (Ernst et al, 2010;Nikoloski et al, 2010). EZH2 draws special attention since it is located on the long arm of chromosome 7 (7q) where deletion of this chromosome is recognized as an adverse cytogenetic marker in AML (Dohner et al, 1998).…”

Molecular characterization of a myelodysplasia‐associated chromosome 7 inversion

“…The distal inversion breakpoint is also close, but slightly centromeric, to the distal breakpoint of the inversion carried in the GF-D8 cell line also defined by the same author. In addition, it is slightly centromeric to the MDR defined at 7q35±q36 and the translocation breakpoint localized to 7q35 by Dohner et al (1998) (our breakpoint lies between clones HSC7E190 and HSC7E630 used in that study), although it is in a region that was lost in nine out of 12 patients.…”