| 1. |
- Andersson, Anna, et al.
(författare)
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Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations
- 2005
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 19:6, s. 1042-1050
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Davidsson, Josef, et al.
(författare)
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Tiling resolution array comparative genomic hybridization, expression and methylation analyses of dup(1q) in Burkitt lymphomas and pediatric high hyperdiploid acute lymphoblastic leukemias reveal clustered near-centromeric breakpoints and overexpression of genes in 1q22-32.3
- 2007
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:18, s. 2215-2225
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Tidskriftsartikel (refereegranskat)abstract
- Although gain of 1q occurs in 25% of Burkitt lymphomas (BLs) and 10% of pediatric high hyperdiploid acute lymphoblastic leukemias (ALLs), little is known about the origin, molecular genetic characteristics and functional outcome of dup(1q) in these disorders. Ten dup(1q)-positive BLs/ALLs were investigated by tiling resolution (32k) array CGH analysis, which revealed that the proximal breakpoints in all cases were near-centromeric, in eight of them clustering within a 1.4 Mb segment in 1q12-21.1. The 1q distal breakpoints were heterogeneous, being more distal in the ALLs than in the BLs. The minimally gained segments in the ALLs and BLs were 57.4 Mb [dup(1)(q22q32.3)] and 35 Mb [dup(1)(q12q25.2)], respectively. Satellite 11 DNA on 1q was not hypomethylated, as ascertained by Southern blot analyses of 15 BLs/ALLs with and without gain of 1q, indicating that aberrant methylation was not involved in the origin of dup(1q), as previously suggested for other neoplasms with 1q rearrangements. Global gene expression analyses revealed that five genes in the minimally 57.4 Mb gained region-B4GALT3, DAP3, RGS16, TMEM183A and UCK2-were significantly overexpressed in dup(1q)-positive ALLs compared with high hyperdiploid ALLs without dup(1q). The DAP3 and UCK2 genes were among the most overexpressed genes in the BL case with gain of 1q investigated. The DAP3 protein has been reported to be highly expressed in invasive glioblastoma multiforme cells, whereas expression of the UCK2 protein has been correlated with sensitivity to anticancer drugs. However, involvement of these genes in dup(1q)-positive ALLs and BLs has previously not been reported.
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| 3. |
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| 4. |
- Lindgren, David, et al.
(författare)
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Recurrent and multiple bladder tumors show conserved expression profiles.
- 2008
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 8:June 30
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Urothelial carcinomas originate from the epithelial cells of the inner lining of the bladder and may appear as single or as multiple synchronous tumors. Patients with urothelial carcinomas frequently show recurrences after treatment making follow-up necessary. The leading hypothesis explaining the origin of meta- and synchronous tumors assumes a monoclonal origin. However, the genetic relationship among consecutive tumors has been shown to be complex in as much as the genetic evolution does not adhere to the chronological appearance of the metachronous tumors. Consequently, genetically less evolved tumors may appear chronologically later than genetically related but more evolved tumors. METHODS: Forty-nine meta- or synchronous urothelial tumors from 22 patients were analyzed using expression profiling, conventional CGH, LOH, and mutation analyses. RESULTS: We show by CGH that partial chromosomal losses in the initial tumors may not be present in the recurring tumors, by LOH that different haplotypes may be lost and that detected regions of LOH may be smaller in recurring tumors, and that mutations present in the initial tumor may not be present in the recurring ones. In contrast we show that despite apparent genomic differences, the recurrent and multiple bladder tumors from the same patients display remarkably similar expression profiles. CONCLUSION: Our findings show that even though the vast majority of the analyzed meta- and synchronous tumors from the same patients are not likely to have originated directly from the preceding tumor they still show remarkably similar expressions profiles. The presented data suggests that an expression profile is established early in tumor development and that this profile is stable and maintained in recurring tumors.
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