Alterations of common chromosome fragile sites in hematopoietic malignancies

Conditions of replication stress affect expression of all common fragile regions, including FRA3B (chromosome 3p14.2), FRA16D (16q23), FRA6E (6q26), FRA7G (7q31.2), and FRAXB (Xp22.3), and a number of cancer cell lines exhibit homozygous deletions in 2 or more common fragile regions. In 1996 the fragile histidine triad (FHIT) gene was isolated from the region encompassing the most active fragile FRA3B locus, and recently the WW domain-containing oxidoreductase gene (WWOX) was identified at FRA16D. These 2 fragile genes are altered or deleted in various epithelial tumors and exhibit tumor suppressor function. Aberration or absence of WWOX expression recently was detected in primary hematopoietic malignancies. The aberration resulted not only from genomic deletions but also possibly from epigenetic modifications associated with expression of fragility. Thus chromosomal aberrations at common fragile sites, in addition to the well-defined hallmark leukemia chromosome translocations, are involved in clinicopathological outcomes of hematopoietic malignancies.