Gains, losses and complex karyotypes in myeloid disorders: a light at the end of the tunnel

Abstract

Complex karyotypes are seen in approximately 15% of de novo MDS/AML and in up to 50% of therapy-related MDS/AML. These patients represent a therapeutic challenge for which no current treatment approach is satisfactory. Therefore, a large number of genetic studies using cytogenetic molecular techniques have been performed to better define the chromosomal abnormalities in this poor-prognosis group. On the basis of the available data from several studies of AML with complex karyotypes, similar findings on recurrent breakpoints and frequently lost and gained chromosomal regions have been observed. The most frequent rearrangements, in all the published series, were unbalanced translocations leading to loss of chromosomal material. Overall, loss of 5q and/or 7q chromosomal material seemed the more common event, and losses of 5q, 7q, and 17p in combination were observed in many cases. Overrepresented chromosomal material from 8q, 11q23, 21q and 22q was found recurrently and in several cases this was due to the amplification of the MLL (located at 11q23) and AML1/RUNX1 (located at 22q22) genes. As a result of these findings, the presence of MLL copy gain/amplifications or losses of the short arm of chromosome 17, in association with 5/5q, have been found to be indicators of an extremely poor prognosis. Interestingly, this non-random pattern of DNA gains and losses, that characterizes AML cases with complex karyotypes, affects the gene expression pattern, and a specific expression profile, characterized by the upregulation of genes involved in the DNA repair and chromosome segregation pathways, has been recently reported. Therefore, a comprehensive genome-wide analysis of patients with AML or MDS with complex karyotypes has led to a better characterization of chromosomal aberrations. These specific alterations could be used in the near future as therapeutic targets or markers for the risk stratification of patients, detection of minimal residual disease and the development of new therapeutic interventions.