Gain of chromosomal material

Duplication of segments of 1q

Duplication of part of 1q has been demonstrated in a number of patients with MPD as well as other myeloid malignancies. It has been found at all stages of disease progression, including at diagnosis. Dupl(1q) was found in both erythroid and myeloid precursors of an MPD patient, confirming its origin within a multipotent progenitor. A common duplicated region ¡spanning 1q23-q32 has been identified but, as yet, no molecular analysis has been undertaken. Duplication of the long arm of chromosome 1 can also result from a non-reciprocal translocation. For example, der(1)t(1;9) leads to trisomy 1q and 9p, both of which may be pathogenetically important. Similarly, monosomy 7 and der(1)t(1;7) results in monosomy 7q and trisomy 1q.

Trisomy 8

Trisomy 8 has been detected in 10-15% of patients with MDS, 5% of AML patients and in 35% of patients with CML blast crisis. The detection of trisomy 8 is particularly amenable to FISH-based techniques using centromeric probes and chromosome painting, which are particularly useful for the analysis of samples in which metaphases are absent or of poor quality.

The use of such techniques has provided a number of interesting observations. Firstly, in some patients it has been suggested that cells with trisomy 8 have a proliferative advantage over normal cells, at least in culture, since the frequency of trisomy 8 cells is greater in bone marrow metaphases than in interphase nuclei. Secondly, trisomy 8 has been detected in minor subclones of a small number of patients for whom conventional karyotyping showed no such aberration, indicating that trisomy 8 may be present in a greater proportion of patients than originally thought. As far as MPD is concerned,

Single critical gene

Normal progenitor

Multiple critical genes

Normal progenitor

Single critical gene

Normal progenitor

Multiple critical genes

Normal progenitor

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w

N

o

o

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Gene inactivation

'One hit' model

'One hit' model

'Two hit' model I

Gene inactivation

'One hit' model

'Two hit' model I

Gene inactivation

'One hit' model

'Two hit' model I

Gene inactivation

Fig. 9.6 Potential mechanism of the pathogenesis of deletions

(a) If there is a single target gene, for example, on chromosome 20q (•) it may be necessary for both copies to be lost/inactivated (two-hit model). Alternatively, loss of a single copy (haploinsufficiency) may be adequate to produce a phenotypic effect (one-hit model). (b) If there is more than one target gene, the one-hit model would entail haploinsufficiency for two or more genes, perhaps scattered over a large distance of the chromosome. In contrast, the two-hit model would involve biallelic inactivation of at least one of the target genes. Adapted from Asimakopoulos and Green (1996) with permission from Blackwell Science.

initial observations of subclones containing trisomy 8 in one-quarter of patients have not been confirmed by larger studies.

Combining FISH with immunophenotyping, it has been possible to follow the lineage involvement of trisomy 8. Price et al. (1992) demonstrated trisomy 8 in the majority of BFU-E and CFU-GM colonies from two patients with PV and trisomy 8. Furthermore, trisomy 8 was present in CD34+ cells and mature myeloid cells but not in lymphoid cells. In AML patients, trisomy 8 has been detected in multipotent progeni tor cells as well as in a subpopulation of flow-sorted lymphoid and erythroid cells. Therefore, it seems likely that, in MPD and MDS, trisomy 8, like del(20q), arises in primitive progenitor cells with myeloid and lymphoid potential. The genetic consequence of chromosome 8 amplification is not clear as no molecular mapping has yet been undertaken.

Abnormality of chromosome 9

As was the case for trisomy 8, suggestions that trisomy 9 may be present in a significant number of patients with MPD have not been substantiated. However, most FISH studies use a chromosome 9 centromere probe and so amplification involving either the short or long arm only may be missed. As described above, trisomy 9p resulting from an unbalanced translocation with chromosome 1 is a recognized abnormality in MPD and gain of 9p due to other mechanisms has also been reported, suggesting that this region may be pathoge-netically important. Interestingly, LOH of a large part of 9p has been demonstrated in six out of 20 patients with PV. No loss of material was observed in these patients, indicating that mitotic recombination rather than deletion was responsible for the 9p LOH. One gene from this region, NFI-B, was found to be overexpressed in patients with 9p LOH, but its pathoge-netic significance remains unclear.

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