gENE ExPRESSION DOWN REgUlATION IN THE INTRINSIC APOPTOSIS PATHWAy DURINg FOllOW-UP OF PATIENTS WITH ACUTE MyElOID lEUkEMIA

Manuscript submitted 74 AbSTRACT Purpose By expression profiling of 31 apoptosis related genes in acute myeloid leukemia (AML) during the course of the disease we determined whether relapse is caused by emergence of apoptosis resistant subpopulations at diagnosis. Experimental design Samples were obtained from patients diagnosed with AML; 40 at diagnosis, 35 during follow-up and 20 at relapse. Blasts were isolated by FACS-sorting based on leukemia associated phenotypes. Reverse Transcriptase-Multiplex Ligation dependent Probe Amplification was applied for simultaneous quantification of transcripts. Transcript levels were compared between the different subgroups at all time points. Sequential correlations were estimated by mixed effects modelling. Results Pro-and anti-apoptotic expression at diagnosis was higher than controls, both in refrac-tory (p=.004, p=.028) and non-refractory patients (p=.001, p=.07). Non-refractory patients showed a decline in expression in response to chemotherapy for pro-apoptotic (p=.028), but not for anti-apoptotic genes (p=.51). Refractory patients showed no change in gene expression in response to chemotherapy, levels remained higher compared to the controls (p=.001, p=.014). At relapse, pro-apoptotic gene expression was higher (p=.019), while anti-apoptotic gene expression remained in the ranges of controls. Conclusions Activation of the apoptosis pathway, expressed by high expression of both pro-and anti-apoptotic genes, is affected by chemotherapy and post-therapy changes.