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(From Bench et al.,69 and references therein, with permission.)

in untreated patients (17 percent),32 although it is not known whether this reflects the leukemogenic effects of the treatment regimens themselves or may indicate that patients whose disease is progressive (and therefore requiring more aggressive therapy) are more likely to develop cytogenetic changes.

Some chromosomal changes, such as deletions or monosomies of chromosomes 5 and 7, are almost invariably seen after exposure to myelosuppressive therapy and frequently as part of a complex karyotype. It is therefore unlikely that these chromosomes contain genes involved in the etiology of the MPDs. By contrast, deletions of part of the long arm of chromosome 20 (del 20q) and 13 (del 13q), trisomies of chromosomes 8 and 9, and duplication of the long arm of chromosome 1 have all been seen in untreated patients and are frequently present as sole abnormalities. They are likely, therefore, to mark the site of genes that play an early role in the pathogenesis of the MPDs.

Deletions of Chromosome 20

After t(9;22), del(20q) was the most common sole structural chromosomal abnormality observed in a series of almost 3000 consecutive bone marrow samples analyzed by G-banding at the Mayo clinic,71 and is the most common cytogenetic abnormality in PV. 20q deletions occur in approximately 8 percent of patients with PV (Table 9-1) but also occur in other MPDs, in 4 percent of patients with myelodysplastic syndromes (MDS), and in 1 to 2 percent of patients with AML.72 Loss of loci on 20q has also been demonstrated in the transition from chronic phase to blast crisis in 5 of 17 CML patients73 but deletions of 20q are rarely seen in lymphoid malignancies. Thus a pattern of disease association suggests that the deleted region of chromosome 20 marks the site of one or more genes, loss or inactiva-tion of which perturb the regulation of hematopoietic progenitors. The finding of 20q deletions at diagnosis and as a sole abnormality suggests that, in at least some cases, it plays an early role in disease pathogenesis.

In patients with PV the presence of a 20q deletion does not appear to influence survival, although the number of patients studied is small.74-76 The 20q deletion can arise in a very early progenitor with both lymphoid and myeloid potential,77,78 and the deletions can often be detected in mature peripheral blood granulocytes.79 Molecular analysis of the 20q deletions has been undertaken to identify critical target genes. Fluorescence in situ hybridization (FISH), microsatellite polymerase chain reaction (PCR), and Southern blotting have demonstrated heterogeneity of both the centromeric and telomeric breakpoints77,80,81 implying that the commonly deleted region (CDR) contains one or more tumor suppressor genes. Physical maps of this region of chromosome 20, in the form of yeast artificial chromosome (YAC) or P1-derived/bacterial artificial chromosome (PAC/BAC) maps82,83 have been constructed to facilitate gene identification. As 20q deletions occur in a number of myeloid disorders it has been necessary to construct disease specific maps. The most recent MPD CDR spans a distance of 2.7 Mb and overlaps with the CDR generated in MDS/AML of 2.6 Mb, giving a combined "myeloid" CDR of 1.7 Mb84 (Figure 9-2). Five genes and 11 unique expressed sequence tags (ESTs) are present in this overlap region. A separate CDR of 250 kb, containing five characterized genes, four predicted genes, and nine single ESTs, has been constructed using information from unbalanced translocations involving loss of 20q sequences from two non-MPD patients, one with MDS the other AML85 (Figure 9-2). Expression profiling of the genes in CD34+ cells has been used to prioritize the MPD CDR for mutational analysis, and candidates from both regions are currently undergoing mutational analysis to identify any tumor suppressor gene.

Analysis of other structural chromosomal abnormalities in PV and the MPDs are at a less advanced stage. A common deleted region has been constructed for 13q deletions in all myeloid disorders86 and specifically for IMF.87 This region involves the minimally deleted region also seen in chronic lymphocytic leukemia (CLL) and other low-grade lymphoproliferative disorders although it is not clear whether the same tumor suppressor gene(s) are affected in myeloid and lymphoid disorders.

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