Identification of Genes Potentially Involved in Disease Transformation of CML.

In patients with chronic myeloid leukemia who do not reach a (near) complete cytogenetic response upon treatment, the disease progresses over months to several years from an indolent, chronic phase into a rapidly fatal blast crisis. Events that are responsible for this transformation process are largely unknown. To identify changes occurring in the course of the disease, we performed cDNA subtraction on sequentially stored peripheral blood mononuclear cell pellets, collected from a single CML patient throughout the course of disease. Thirty-three differentially expressed sequences were identified, of which 28 corresponded to known genes. Quantitative PCR confirmed cDNA subtraction results for 24 of 25 tested genes. Differential expression levels ranged from <2- to 106-fold. The sequences that were identified include genes encoding for several apoptosis related proteins, cell cycle proteins, interleukins/chemokines, heat shock proteins and a DNA repair enzyme (see table). Thus far, expression levels of eight genes have been tested in sequential samples of three to six additional CML patients, gathered throughout their disease course. PBCEF, IL8, IL6, CCL4 and YWHAZ show comparable patterns as the index patient; expression levels of APEX, NXF1 and PRG1 were consistent with those of the index patient in only a part of the additional patients. More patients are being tested on these and remaining genes. We conclude that this set of genes can be considered as a valuable starting point for further research on the causes of disease transformation in CML.