Molecular genetics and cytogenetics of myeloproliferative disorders

The myeloproliferative disorders are believed to represent clonal malignanc ies resulting from transformation of a pluripotent stem cell. X-inactivatio n patterns of peripheral blood cells have been proposed as a useful diagnos tic tool but this method is limited by the finding of a clonal X-inactivati on pattern in a significant proportion of normal elderly women. There is no pathognomonic chromosomal abnormality associated with the myeloproliferati ve disorders. However, consistent acquired cytogenetic changes include del( 20q), del(13q), trisomy 8 and 9 and duplication of segments of 1q, all of w hich have been observed at diagnosis or before cytoreductive therapy and th erefore represent early lesions which contribute to the pathogenesis of the se disorders. Although, the acquired molecular defects underlying most myel oproliferative disorders have not yet been elucidated, translocations assoc iated with the rare 8p11 syndrome have permitted identification of a novel fusion protein. The role of a number of candidate genes in the other myelop roliferative disorders has also been studied, but no mutations have been id entified so far. It is likely that a number of genes will be involved, give n the varied phenotypes of the diseases. Identification of causal genes wil l be of considerable interest to both clinicians, who currently lack a spec ific and sensitive diagnostic test, and scientists interested in fundamenta l issues of stem cell behaviour.