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| 2. |
- 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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| 3. |
- Andersson, Anna, et al.
(författare)
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Microarray-based classification of a consecutive series of 121 childhood acute leukemias: prediction of leukemic and genetic subtype as well as of minimal residual disease status.
- 2007
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 21:6, s. 1198-1203
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression analyses were performed on 121 consecutive childhood leukemias (87 B-lineage acute lymphoblastic leukemias (ALLs), 11 T-cell ALLs and 23 acute myeloid leukemias (AMLs)), investigated during an 8-year period at a single center. The supervised learning algorithm k-nearest neighbor was utilized to build gene expression predictors that could classify the ALLs/AMLs according to clinically important subtypes with high accuracy. Validation experiments in an independent data set verified the high prediction accuracies of our classifiers. B-lineage ALLs with uncharacteristic cytogenetic aberrations or with a normal karyotype displayed heterogeneous gene expression profiles, resulting in low prediction accuracies. Minimal residual disease status (MRD) in T-cell ALLs with a high (40.1%) MRD at day 29 could be classified with 100% accuracy already at the time of diagnosis. In pediatric leukemias with uncharacteristic cytogenetic aberrations or with a normal karyotype, unsupervised analysis identified two novel subgroups: one consisting mainly of cases remaining in complete remission (CR) and one containing a few patients in CR and all but one of the patients who relapsed. This study of a consecutive series of childhood leukemias confirms and extends further previous reports demonstrating that global gene expression profiling provides a valuable tool for genetic and clinical classification of childhood leukemias.
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| 4. |
- Andreasson, Patrik, et al.
(författare)
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Cytogenetic and FISH studies of a single center consecutive series of 152 childhood acute lymphoblastic leukemias
- 2000
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 65:1, s. 40-51
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Tidskriftsartikel (refereegranskat)abstract
- Between 1977 and 1996, cytogenetic investigations were performed on 182 childhood (< or = 16 yr) acute lymphoblastic leukemias (ALL), constituting 94% (182 of 194) of all ALL patients diagnosed and treated at the Departments of Pediatrics, Lund and Malmo University Hospitals, Sweden, during these two decades. The cytogenetic analyses were successful in 152 cases (84%). The failure rate was higher for the ALL investigated before 1987 (30% vs. 4%, p < 0.0001), and also the incidence of cytogenetically normal cases was higher during 1977-86 (43% vs. 25%, p < 0.05). Clonal chromosomal abnormalities were found in 103 (68%) ALL. Structural rearrangements were detected, by chromosome banding alone, in 76 cases (50%). Fluorescence in situ hybridization (FISH) was used to identify cases with t(12;21), 11q23 rearrangements, and 9p deletions, using probes for ETV6/CBFA2, MLL, and CDKN2A/B, in 72 cases from which cells in fixative and/or unstained metaphase preparations were available. In total, the most common structural rearrangements were del(9p) (17%), t(12;21) (15%), del(6q) (8%), and MLL rearrangements (4%). Six (32%) of nineteen cytogenetically normal ALL analyzed by FISH harbored cryptic abnormalities; three displayed t(12;21) and four had del(9p), one of which also carried a t(12;21). Five (45%) of the t(12;21)-positive ALL showed +der(21)t(12;21) or ider(21)(q10)t(12;21), resulting in the formation of double fusion genes. Among the more rare aberrations, eight structural rearrangements were identified as novel recurrent ALL-associated abnormalities, and nine cases harbored rearrangements previously not reported. Sixteen cases displayed karyotypically unrelated clones at different investigations. Seven ALL (5%) showed simple chromosomal changes, unrelated to the aberrations detected at diagnosis, during morphologic and clinical remission, and in all but one instance the patients remained in remission, with the abnormal clone disappearing in subsequent investigations. This indicates that the emergence of novel clonal chromosomal aberrations during remission in childhood ALL is rather common and does not by necessity predict a forthcoming relapse.
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| 5. |
- Davidsson, Josef, et al.
(författare)
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The DNA methylome of pediatric acute lymphoblastic leukemia
- 2009
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Ingår i: HUMAN MOLECULAR GENETICS. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:21, s. 4054-4065
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Tidskriftsartikel (refereegranskat)abstract
- Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with high hyperdiploidy [51-67 chromosomes] and the t(12;21)(p13;q22) [ETV6/RUNX1 fusion] representing the most frequent abnormalities. Although these arise in utero, there is long latency before overt ALL, showing that additional changes are needed. Gene dysregulation through hypermethylation may be such an event; however, this has not previously been investigated in a detailed fashion. We performed genome-wide methylation profiling using bacterial artificial chromosome arrays and promoter-specific analyses of high hyperdiploid and ETV6/RUNX1-positive ALLs. In addition, global gene expression analyses were performed to identify associated expression patterns. Unsupervised cluster and principal component analyses of the chromosome-wide methylome profiles could successfully subgroup the two genetic ALL types. Analysis of all currently known promoter-specific CpG islands demonstrated that several B-cell- and neoplasia-associated genes were hypermethylated and underexpressed, indicating that aberrant methylation plays a significant leukemogenic role. Interestingly, methylation hotspots were associated with chromosome bands predicted to harbor imprinted genes and the tri-/tetrasomic chromosomes in the high hyperdiploid ALLs were less methylated than their disomic counterparts. Decreased methylation of gained chromosomes is a previously unknown phenomenon that may have ramifications not only for the pathogenesis of high hyperdiploid ALL but also for other disorders with acquired or constitutional numerical chromosome anomalies.
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| 7. |
- 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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| 8. |
- Fogelstrand, Linda, 1974, et al.
(författare)
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Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols
- 2014
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Ingår i: Pediatric Blood & Cancer. - : Wiley-Blackwell. - 1545-5009 .- 1545-5017. ; 61:3, s. 424-430
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Tidskriftsartikel (refereegranskat)abstract
- Background In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.Procedure We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.Results Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen.Conclusions Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.
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| 9. |
- Lilljebjörn, Henrik, et al.
(författare)
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Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region
- 2007
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 21:10, s. 2137-2144
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Tidskriftsartikel (refereegranskat)abstract
- Seventeen ETV6/RUNX1-positive pediatric acute lymphoblastic leukemias were investigated by high-resolution array-based comparative genomic hybridization ( array CGH), gene expression profiling and fluorescence in situ hybridization. Comparing the array CGH and gene expression patterns revealed that genomic imbalances conferred a great impact on the expression of genes in the affected regions. The array CGH analyses identified a high frequency of cytogenetically cryptic genetic changes, for example, del(9p) and del(12p). Interestingly, a duplication of Xq material, varying between 30 and 60Mb in size, was found in 6 of 11 males (55%), but not in females. Genes on Xq were found to have a high expression level in cases with dup(Xq); a similar overexpression was confirmed in t(12;21)-positive cases in an external gene expression data set. By studying the expression profile and the proposed function of genes in the minimally gained region, several candidate target genes (SPANXB, HMGB3, FAM50A, HTATSF1 and RAP2C) were identified. Among them, the testis-specific SPANXB gene was the only one showing a high and uniform overexpression, irrespective of gender and presence of Xq duplication, suggesting that this gene plays an important pathogenetic role in t(12;21)-positive leukemia.
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| 10. |
- Lilljebjörn, Henrik, et al.
(författare)
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The correlation pattern of acquired copy number changes in 164 ETV6/RUNX1-positive childhood acute lymphoblastic leukemias
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 19:16, s. 3150-3158
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Tidskriftsartikel (refereegranskat)abstract
- The ETV6/RUNX1 fusion gene, present in 25% of B-lineage childhood acute lymphoblastic leukemia (ALL), is thought to represent an initiating event, which requires additional genetic changes for leukemia development. To identify additional genetic alterations, 24 ETV6/RUNX1-positive ALLs were analyzed using 500K single nucleotide polymorphism arrays. The results were combined with previously published data sets, allowing us to ascertain genomic copy number aberrations (CNAs) in 164 cases. In total, 45 recurrent CNAs were identified with an average number of 3.5 recurrent changes per case (range 0-13). Twenty-six percent of cases displayed a set of recurrent CNAs identical to that of other cases in the data set. The majority (74%), however, displayed a unique pattern of recurrent CNAs, indicating a large heterogeneity within this ALL subtype. As previously demonstrated, alterations targeting genes involved in B-cell development were common (present in 28% of cases). However, the combined analysis also identified alterations affecting nuclear hormone response (24%) to be a characteristic feature of ETV6/RUNX1-positive ALL. Studying the correlation pattern of the CNAs allowed us to highlight significant positive and negative correlations between specific aberrations. Furthermore, oncogenetic tree models identified ETV6, CDKN2A/B, PAX5, del(6q) and +16 as possible early events in the leukemogenic process.
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