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FA stem cells and progenitor cells are apoptotic in the ground state and hypersensitive to a variety of extracellular apoptotic cues. The relative lifetime risk of AML or MDS in FA is high and clonal cytogenetic defects are universally found in evolved clones, but the mechanisms involved in leukemogenesis are unknown. The combined influences of genetic instability and high level stem cell apoptosis represents a de-facto selective pressure that in our view favors the emergence of more resistant stem cell clones. Predictions of this model are: (1) Non clonal FA progenitor cells (FAwt) are hypersensitive to apoptotic cues but FA progenitors derived from cytogenetically abnormal clones (FAclon) will be resistant, (2) anti-apoptotic events that attend cytogenetic clonal evolution should interdict precisely those apoptotic pathways activated by FA gene mutations, and (3) Key transcripts differentially expressed in the normal (N) vs. FAwt comparison should normalize (ie. should register as "no change") in the N vs. FAclon comparison. Preliminary studies support the first 2 predictions (Lensch et al, Leukemia, 1999 and Haneline et al, Blood, 2003). To further test the adaptive model, we compared transcriptomes of 41 low density bone marrow cell samples: (11 normal volunteers [N], 9 FAclon [marrow replaced [>75%] by cells bearing clonal cytogenetic defects] and 21 FAwt [no cytogenetic abnormalities]). RNA was prepared in the participating institutions and shipped to Portland on dry ice. Complementary DNA and cRNA was prepared, cRNA fragments labeled for use as targets of the probes in the human U133A Affymetrix chip. MAS 5.0 was utilized to process images, quantify signals, adjust background, and to scale the data. A linear mixed model was used for inter-chip normalization. Unsupervised hierarchical clustering and multidimensional scaling (MDS) distinguished N from FAwt samples but FAclon fell within the mathematical space defined by the N RNA. Of 17,044 genes tested, 1,430 were expressed differentially (FDR adjusted p