Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations

Summary, in English

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 leukemogenesis. 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. Furthermore, the expression profile of tyrosine kinase-encoding genes was investigated, identifying several differentially expressed members, segregating with primary genetic changes, which may be targeted with tyrosine kinase inhibitors. The identified conserved signatures are likely to reflect regulatory networks of importance for the transforming abilities of the primary genetic changes and offer important pathogenetic insights as well as a number of targets for future rational drug design.

• Författare: Anna Andersson; Patrik Edén; David Lindgren; Jens Nilsson; Carin Lassen; Jesper Heldrup; Magnus Fontes; Åke Borg; Felix Mitelman; Bertil Johansson; Mattias Höglund; Thoas Fioretos
• Avdelning/ar: Avdelningen för klinisk genetik; Beräkningsbiologi och biologisk fysik - Har omorganiserats; Bröstcancer-genetik; Matematik LTH; Pediatrik, Lund; MLL-rearrangerad leukemi hos spädbarn
• Publiceringsår: 2005
• Språk: Engelska
• Sidor: 1042-1050
• Publikation/Tidskrift/Serie: Leukemia
• Volym: 19
• Issue: 6
• Länkar: http://dx.doi.org/10.1038/sj.leu.2403749
• Dokumenttyp: Artikel i tidskrift
• Förlag: Nature Publishing Group
• Ämne: Cancer and Oncology
• Nyckelord: cDNA microarray; AML; CML-BC; ALL; pediatric leukemia
• Status: Published
• Forskningsgrupp: The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy
• ISBN/ISSN/Övrigt: ISSN: 1476-5551