Spectral Karyotyping (SKY) of Hematologic Malignancies

The discovery of the Philadelphia chromosome in chronic myeloid leukemia (CML) by Novell and Hungerford in 1960 (1), the subsequent clarification of this chromosomal abnormality as areciprocal translocation t(9;22)(q34;q1 1) by Rowley in 1973 (2), the identification of the genes involved at the translocation breakpoints (3,4), and ultimately the demonstration of the leukemogenic activity of the resulting fusion product (5), represent hallmarks for our understanding of malignant diseases as genetic disorders. The elucidation of the Philadelphia translocation emphasizes the importance of cytogenetic analysis of hematologic malignancies. Clarification of this chromosomal aberration as a reciprocal translocation became only possible after the development of cytogenetic banding techniques by Caspersson et al. in 1970 (6). Chromosome banding analysis revealed numerous nonrandom chromosomal aberrations, particularly balanced translocations in leukemias and lymphomas, e.g., the translocation t(8;21)(q22;q22) in acute myeloid leukemia (AML) first described by Rowley et al. in 1973 (7). These balanced translocations were shown to be of etiologic as well as diagnostic, prognostic, and therapeutic importance. They result in an altered gene function by two main mechanisms: (1) sequences of, in most instances, a transcription factor or receptor tyrosine kinase gene are fused to a normally unrelated gene, creating specific fusion proteins with oncogenic properties, and (2) protooncogenes are repositioned to the vicinity of promoter/enhancer elements of the immunoglobulin- or T-cell receptor genes, thereby initiating their activation (8).