Transcriptome profiling of fenretinide-treated and untreated CD34+ cells from 4 CML patients

Imatinib, as the first-line agent of chronic myeloid leukemia (CML), is ineffective in eradicating CML stem/progenitor cells, thus unable to prevent late relapse. Here we present data indicating that fenretinide preferentially targets CD34+ CML cells and enhances the efficacy of imatinib in CML. As tested by colony forming cell assays, both number and size of total colonies derived from CD34+ CML cells were significantly reduced by fenretinide, and by combining fenretinide with imatinib. In particular, colonies derived from erythroid progenitors and those derived from more primitive pluripotent progenitor cells were highly sensitive to fenretinide/fenretinide plus immtinib. Further data showed that fenretinide was able to induce apoptosis in CD34+ CML cells which were refractory to imatinib. Through transcriptome analysis and followed by molecular validation, we further showed that apoptosis induced by fenretinide in CD34+ CML cells was mediated by complex mechanisms of stress responses, probably triggered by elevated levels of intracellular reactive oxygen species. Thus, fenretinide combines with imatinib may represent a new strategy for the treatment of CML, in which fenretinide targets primitive CD34+ CML cells whereas imatinib targets leukemic blasts. This strategy may eventually reduce the risk of relapse and probably resistant as well in CML patients. Transcriptome profiles of CML CD34+ cells with and without fenretinide treatment were analyzed using whole genome expression arrays (Affymetrix HG-U133 Plus 2.0) in four CML patients (CML32, CML33, CML34 and CML35, see Table 1). To minimize potential data biases, both treated and untreated cell samples were maintained in culture for 48 hours before hybridization.