A. Andersson, P. Edén, D. Lindgren, J. Nilsson, C. Lassen, J. Heldrup, M. Fontes, Å. Borg, F. Mittelman, B. Johansson, M. Höglund and T. Fioretos
Gene Expression Profiling of Leukemic Cell Lines Reveals Conserved Molecular Signatures among Subtypes with Specific Genetic Aberrations
to appear in Leukemia

Hematologic malignancies are characterized by fusion genes of biological/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of lukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23/MLL rearrangements, t(1;19)[TCF3/PBX1], t(12;21)[ETV6/RUNX1], t(8;21)[RUNX1/CBFA2T1], t(8;14)[IGH@/MYC], t(8;14)[TRA@/MYC], t(9;22)[BCR/ABL1], t(10;11)[PICALM/MLLT10], t(15;17)[PMl/RARA] or inv(16)[CBFB/MYH11]. Unsupervised classification revealed that hematopoietic cell lines of diverse origin, but with the same primary genetic changes, segregated together, suggesting that pathogenetically important regulatory networks remain conserved despite numerous passages. Moreover, primary leukemias cosegregated with cell lines carrying identical genetic rearrangements, further supporting that critical regulatory pathways remain intact in hematopoietic cell lines. Transcriptional signatures correlating with clinical subtypes/primary genetic changes were identified and annotated based on their biological/molecular properties and chromosomal localization. Furhtermore, the expression profile of tyorsine kinase-encoding genes was investigated, identifying several differentially expressed members, segregating with primary genetic changes, which may be targeted wigh tyrosine kinase inhibitors. The identified coserved signatures are likely to reflect regulatory networks of importance for the tralsforming abilities of the primary geneitc changes and offer important pathogenetic insights as well as a number of targets for future rational drug design.

LU TP 05-16