Chronic Myelogenous Leukemia (CML). This was followed by the discovery in 1972 that the Philadelphia Chromosome was really a translocation of chromosomes 9 and 22. In 1984 the 9;22 translocation was cloned by Nora Heistercamp and John Grafin who identified the Abelson (ABL) gene on chromosome 9 and the BCR gene on chromosome 22. Subsequent research showed that it was a fusion gene. The final advance, in 1998, was the use of Gleevec, which has turned out to be a miraculous drug for the treatment of many patients with CML. Although the chromosome abnormality was discovered in 1960, the discovery of specific treatment did not occur until 1998, almost a 40-year gap.
We examined leukemic cells from patients with acute myelogenous leukemia, each with a specific chromosome abnormality, namely different translocations, each with a unique morphology. My assumption has always been that this unique morphology is in fact associated with unique patterns of gene expression, and the challenge has been to try to figure out what these patterns are. All the breakpoints have been cloned. At the present time, except for the 15;17 translocation, we do not have genotypic specific therapy for any of these extremely common translocations.
The challenge is how to develop the optimal treatment. This is important from the clinical standpoint because the different chromosome abnormalities have different survivals, so they have prognostic implications. A 1998 study of the Medical Research Council Laboratory of Molecular Biology (MRC) that appeared in Blood, showed that the survival of patients with the recurring translocations I illustrated previously is 60 to 70 percent at 5 years. Surviving patients in general tend to be younger. In contrast, patients with a complex karyotype, loss of 5 or 7, or translocations of chromosome 11 have a dismal survival. These are genotypically different types of leukemia that need different types of therapy.
This raises two issues, one of which is improved diagnosis and the other, improved treatment. It is important to inform the physician of the patient’s likely prognosis, as this will influence treatment. However, we are not going to get to genotype specific treatment until we have better information about the biology of these different leukemias.
To address this issue, Jim Downing’s laboratory at St. Jude has used microarray analyses in childhood acute lymphoblastic leukemia. There is a unique pattern of gene expression in each one of these chromosomely unique types of leukemia. Thus, even using only known genes we can begin to develop diagnostic chips. I emphasize that these are known genes because that is all that are on the present Affymetrix microarrays.
We have taken a different approach and we are using Serial Analysis of Gene Expression (SAGE), which was developed by Ken Kinzler, and his colleague Bert Vogelstein at Johns Hopkins Medical Center. We used 3' mRNA and translated it into cDNA. SAGE uses the NLA III enzyme,