Deletions Flanking The Bcrabl Breakpoint

It was recently observed that 10-15% of CML patients harbor large deletions, flanking the breakpoint on chromosome 9 and, less frequently, chromosome 22, or both.22 23 Patients with such deletions have a much shorter survival with interferon-alpha-based therapy and appear to have a shorter time to progression on imatinib.24 These observations led to the speculation that the deleted region may contain a tumor suppressor gene. One candidate on chromosome 9q is PRDM12, a zinc-finger protein, which may function as a negative transcriptional regulator.25 26 Deletions on the derivative chromosome 9 are detectable with most commercially available FISH probes.27 In addition, patients with loss of genetic material on either side of the breakpoint are negative for ABL-BCR mRNA.28 This however does not fully account for the fact that about one-third of CML patients fail to express this reciprocal fusion mRNA.29 Although the prognostic significance of deletions flanking the BCR-ABL breakpoint awaits evaluation in a prospective fashion, "deletion status" should become part of diagnostic reports.30 It has recently been shown that the frequency of deletions is much higher in patients with so-called variant Ph translocations that involve one or two chromosomes in addition to chromosomes 9 and 22. These variants may be generated at the time of the initial translocation event or, less frequently, may be acquired during disease progression, where they represent an unusual form of clonal cytogenetic evolution (see below).31 The inferior survival of patients with variant Ph translocations could be convincingly attributed to high frequency of derivative chromosome 9 deletions, as elimination of this group of patients eliminated the difference.31

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