A Molecular Cytogenetics Profile of Chromosome 9p in CMPD.

Chronic Myeloproiferative Disorders (CMPDs) form a continuum of haematological malignancies of which the molecular pathogenesis remains obscure. Chronic Myeloid Leukaemia (CML) being the only disorder with a recognisable pathogenomic abnormality, the Ph chromosome. Tyrosine kinases are clearly implicated in the disease pathogenesis, in particular the role of JAK2. It has been shown that over 80% of Polycythaemia Vera (PV) patients and 30% of Essential Thrombocythaemia (ET) patients demonstrate a clonal and recurrent mutation V617F in the JH2 pseudo-kinase domain of JAK2 located on 9p24.1. Array CGH investigations of cell lines, revealed a complex pattern of imbalances affecting the short arm of chromosome 9: on the background of 2–3-fold amplification, a loss of the 9p24.1 region, which harbours the JAK 2 along with a number of other kinases, was repeatedly observed. The aim of this study was to clarify the aCGH observations using a series of BAC DNA probes mapping from the telomere of 9p toward the centromere. Results indicate the presence of imbalances (amplifications & deletions) and rearrangements, involving the region encompassing JAK2. In all CML-BC cell lines the FISH data supports the observation of a relative loss of the 9p24.1 region on the background of amplification of chromosome 9. An on-going study of CMPD and MDS patients with both normal and abnormal karyotypes has revealed imbalances affecting the short arm of chromosome 9. In 23% (7/30) of patients there were imbalances; the majority of these (56%) demonstrated a relative loss of information in this region. The pathegenomic significance of imbalances involving 9p remains unclear. It may however represent an acquired homozygousity as a consequence of mitotic recombination, with a ‘second hit’ removing a wild type allele, leading on to further, as yet un-clarified changes.