| 1. |
- Andersson, A., et al.
(författare)
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FLT3 mutations in a 10 year consecutive series of 177 childhood acute leukemias and their impact on global gene expression patterns
- 2008
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 47:1, s. 64-70
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Tidskriftsartikel (refereegranskat)abstract
- During 1995-2004, 209 children/adolescents were diagnosed with acute lymphoblastic or myeloid leukemia (ALL, AML) in Southern Sweden, of which 177 (85%), comprising 128 B-lineage ALL, 34 AML, and 15 T-cell ALL, could be analyzed for internal tandem duplications (ITD) and activating point mutations in the second tyrosine kinase domain (ATKD) of FLT3. Seventeen (10%) FLT3 mutations (6 ITD, 11 ATKD, mutually exclusive) were detected. None of the T-cell ALL harbored any mutations. ITD and ATKD were found in 2% and 6% of the B-lineage ALL and in 12% and 9% of the AML, being particularly common in high hyperdiploid ALL (14%), ALL (20%), and AML (23%) with 11q23/MLL rearrangements, and in AML with a normal karyotype (60%). All ATKD-positive AML with MLL rearrangements harbored the t(9,11)(p21,q23). Global gene expression data were available for 76 of the B-lineage ALL and 19 of the AML, of which 6 (8%) and 3 (16%) had FLT3 mutations, respectively. No distinct expression pattern associated with FLT3 mutations was identified. © 2007 Wiley-Liss, Inc.
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| 2. |
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| 3. |
- Biloglav, Andrea, et al.
(författare)
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SFPQ-ABL1-positive B-cell precursor acute lymphoblastic leukemias
- 2020
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264.
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, a subgroup of B‐cell precursor acute lymphoblastic leukemia (BCP ALL) without an established abnormality (“B‐other”) has been shown to be characterized by rearrangements of ABL1 , ABL2 , CSF1R , or PDGFRB (a.k.a. ABL‐class genes). Using FISH with probes for these genes, we screened 55 pediatric and 50 adult B‐other cases. Three (6%) of the adult but none of the childhood B‐other cases were positive for ABL‐class aberrations. RT‐PCR and sequencing confirmed a rare SFPQ‐ABL1 fusion in one adult B‐other case with t(1;9)(p34;q34). Only six SFPQ ‐ABL1 ‐positive BCP ALLs have been reported, present case included. A review of these shows that all harbored fusions between exon 9 of SFPQ and exon 4 of ABL1 , that the fusion is typically found in adolescents/younger adults without hyperleukocytosis, and that IKZF1 deletions are recurrent. The few patients not treated with tyrosine kinase inhibitors (TKIs) and/or allogeneic stem cell transplantation relapsed, strengthening the notion that TKI should be added to the therapy of SFPQ ‐ABL1 ‐positive BCP ALL.
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| 4. |
- Hallor, Karolin Hansén, et al.
(författare)
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Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma
- 2005
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 44:1, s. 97-102
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Tidskriftsartikel (refereegranskat)abstract
- Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that usually occurs in children and young adults. Only two cases of AFH with genetic rearrangements have been reported previously; both of these had a FUS-ATF1 fusion gene. We have studied an AFH from a 9-year-old boy whose tumor displayed a t(12;22)(q13;q12) as the sole cytogenetic aberration. FISH,RT-PCR, and sequence analyses revealed an EWSR1-ATF1 fusion gene that has previously been reported in clear cell sarcoma (CCS), a soft tissue sarcoma that is morphologically and clinically distinct from AFH. This study thus has demonstrated that the EWSR1-ATF1 chimera represents a fusion gene that can be associated with different tumor types. Simultaneous expression of the EWSR1-ATF1 and MITF-M transcripts in CCS has led to the proposal that the MITF-M promoter is transactivated by EWSR1-ATF1. The AFH, however, did not express the MITF-M transcript, supporting the theory that MITF-M expression in CCS is a reflection of its cellular origin, rather than a consequence of the presence of an EWSR1-ATF1 fusion protein. Activation of the EWSR1-ATF1 oncogene is probably an early step in the transformation process, but the overall gene expression patterns are likely to vary considerably between AFH and CCS, in keeping with their clinicopathologic differences.
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| 5. |
- Lundin, Catarina, et al.
(författare)
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High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - Malden : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 51:2, s. 196-206
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Tidskriftsartikel (refereegranskat)abstract
- Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as less than10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrentdup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.
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| 6. |
- Lundin, Catarina, et al.
(författare)
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Submicroscopic genomic imbalances in burkitt lymphomas/leukemias : Association with age and further evidence that 8q24/MYC translocations are not sufficient for leukemogenesis
- 2013
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 52:4, s. 370-377
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome banding analyses reveal secondary chromosome abnormalities in addition to the MYC translocations t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11;q24) in 60%80% of Burkitt lymphomas/leukemias (BL). The high incidence of such aberrations indicates that additional changes are important, perhaps necessary, for malignant transformation, i.e., the 8q24/MYC rearrangements may not be sufficient. To investigate this possibility, we performed single nucleotide polymorphism (SNP) array analysis on 20 cases of 8q24/MYC-positive BL. Nineteen (95%) harbored genomic imbalances; the only case without such aberrations displayed secondary changes by chromosome banding analysis. Thus, all BL cases had abnormalities in addition to the 8q24 translocation. The adult cases harbored more changes (median 3; range 121) than did the childhood cases (median 1.5; range 05) (P = 0.034). Several recurrent aberrations were detected by SNP array analysis, in particular losses of 6q14.1-q22.33, 9p21.3, and 13q14.2-q14.3, gains of 1q23.3-q31.3, chromosome 7, 13q31.3, and partial uniparental isodisomies for 6p12.2-pter, 9p23-pter, and 17p11.2-pter. The molecular genetic consequences of these changes include deletions of the CDKN2A and TP53 genes, and gains/losses of several genes, such as MIR17HG and E2F2K, involved in the MYC pathway. Thus, deregulation of the MYC pathway, both directly through the 8q24/MYC translocation and indirectly through secondary genomic imbalances, may be essential not only for the initiation but also for the progression of BL.
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| 7. |
- Olsson, Linda, et al.
(författare)
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Cooperative Genetic Changes in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia with Deletions or Mutations of IKZF1
- 2015
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley: 12 months. - 1045-2257 .- 1098-2264. ; 54:5, s. 315-325
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Tidskriftsartikel (refereegranskat)abstract
- In contrast to IKZF1 deletions (IKZF1), IKZF1 sequence mutations (mutIKZF1) have been reported to be rare in B-cell precursor acute lymphoblastic leukemia and their clinical implications are unknown. We performed targeted deep sequencing of all exons of IKZF1 in 140 pediatric cases, eight (5.7%) of which harbored a mutIKZF1. The probabilities of relapse (pRel) and event-free survival (pEFS) did not differ between cases with or without mutIKZF1, whereas pEFS was decreased and pRel increased in IKZF1-positive case. Coexisting microdeletions, mutations (FLT3, JAK2, SH2B3, and SPRED1), and rearrangements (ABL1, CRLF2, JAK2, and PDGFRB) in 35 IKZF1 and/or mutIKZF1-positive cases were ascertained using fluorescence in situ hybridization, single nucleotide polymorphism array, Sanger, and targeted deep sequencing analyses. The overall frequencies of copy number alterations did not differ between cases with our without IKZF1/mutIKZF1. Deletions of HIST1, SH2B3, and the pseudoautosomal region (PAR1), associated with deregulation of CRLF2, were more common in IKZF1-positive cases, whereas PAR1 deletions and JAK2 mutations were overrepresented in the combined IKZF1/mutIKZF1 group. There was no significant impact on pRel of the deletions in IKZF1-positive cases or of JAK2 mutations in cases with IKZF1/mutIKZF1. In contrast, the pRel was higher (P=0.005) in IKZF1/mutIKZF1-positive cases with PAR1 deletions. (c) 2015 Wiley Periodicals, Inc.
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| 8. |
- Olsson, Linda, et al.
(författare)
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Improved cytogenetic characterization and risk stratification of pediatric acute lymphoblastic leukemia using single nucleotide polymorphism array analysis : A single center experience of 296 cases
- 2018
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 57:11, s. 604-607
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Tidskriftsartikel (refereegranskat)abstract
- Single nucleotide polymorphism array (SNP-A) analyses are increasingly being introduced in routine genetic diagnostics of acute lymphoblastic leukemia (ALL). Despite this, only few studies that have compared the diagnostic value of SNP-A with conventional chromosome banding have been published. We here report such a comparison of 296 ALL cases, the largest series to date. Only genomic imbalances >5 Mb and microdeletions targeting the BTG1, CDKN2A/B, EBF1, ERG, ETV6, IKZF1, PAX5, and RB1 genes and the pseudoautosomal region 1 (PAR1) were ascertained, in agreement with recent guidelines. Of 36 T-cell ALL cases, the karyotypes of 24 cases (67%) were revised by SNP-A analyses that either revealed additional imbalances >5 Mb or better characterized the changes found by G-banding. Of 260 B-cell precursor (BCP) ALL cases, SNP-A analyses identified additional copy number alterations, including the above-mentioned microdeletions, or better characterized the imbalances found by G-banding in 236 (91%) cases. Furthermore, the cytogenetic subtype classification of 41/260 (16%) BCP ALL cases was revised based on the SNP-A findings. Of the subtype revisions, 12/41 (29%) had clinical implications as regards risk stratifying cytogenetic groups or genotype-specific minimal residual disease stratification. We conclude that SNP-A analyses dramatically improve the cytogenetic characterization of both T-cell and BCP ALL and also provide important information pertinent to risk stratification of BCP ALL.
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| 9. |
- Panagopoulos, Ioannis, et al.
(författare)
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Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22)
- 1994
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 11:4, s. 256-262
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Tidskriftsartikel (refereegranskat)abstract
- It has been shown that the gene ERG in 21q22 is rearranged in the the t(16;21)(p11;q22) associated with acute myeloid leukemia (AML). ERG is a member of the ETS gene family and is fused with EWS in a subset of Ewing's sarcomas. EWS in 22q12 has a very high homology with FUS (also called TLS) in 16p11; the latter gene is rearranged in the t(12;16)(q13;p11) that characterizes myxoid liposarcoma. To investigate whether FUS is involved in the t(16;21) of AML, we used the Southern blot technique and polymerase chain reaction (PCR) to examine the bone marrow of a 3-year-old boy with a t(16;21)(p11;q22)-positive AML. Hybridization of Southern blot filters containing digested DNA with probes for FUS and ERG showed both germline and aberrant fragments. Using specific primers for the 5 part of FUS and the 3 part of ERG, we amplified a 4.4 kb genomic FUS/ERG DNA fragment from the leukemic sample. In a second PCR experiment, in which we used primers upstream of the 5 part of ERG and downstream of the 3 part of FUS, a 5.6 kb fragment was amplified. Blotting and hybridization with specific probes for FUS and ERG revealed that the amplified fragments consisted of FUS/ERG and ERG/FUS hybrid DNA. Both PCR fragments, when used as probes, detected germline ERG and FUS as well as aberrant fragments on Southern blot filters. The results suggest that the t(16;21) in AML leads to rearrangement and fusion of the FUS and ERG genes. This is the first example in which two genes, each known to recombine with other genes in different solid tumor types (FUS in myxoid liposarcoma and ERG in Ewing's sarcoma), are fused in a hematologic malignancy.
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| 10. |
- Paulsson, Kajsa, et al.
(författare)
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Evidence for a single-step mechanism in the origin of hyperdiploid childhood acute lymphoblastic leukemia
- 2005
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 44:2, s. 113-122
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Tidskriftsartikel (refereegranskat)abstract
- High hyperdiploidy (>50 chromosomes) in childhood acute lymphoblastic leukemia (ALL) is characterized by nonrandom multiple trisomies and tetrasomies involving in particular chromosomes X, 4, 6, 8, 10, 14, 17, 18, and 21. This characteristic karyotypic pattern, the most common in pediatric ALL, may arise via a tetraploid state with subsequent loss of chromosomes, by sequential gains of chromosomes in consecutive cell divisions, or by simultaneous gain of chromosomes in a single mitosis. These alternatives may be distinguished by investigation of the allelic ratios of loci on the tetrasomic and disomic chromosomes. Previous studies of tetrasomy 21 and of the occurrence of uniparental disomies (UPDs) have suggested that the most likely mechanism is simultaneous gain. However, the other pathways have not been definitely excluded because complete analyses of all disomies and tetrasomies have never been performed. In the present study, we investigated 27 hyperdiploid ALLs by using 58 polymorphic microsatellite markers mapped to 23 of the 24 human chromosomes. Twenty-six tetrasomies were analyzed (involving chromosomes X, 8, 10, 14, 18, and 21), and the frequency of UPDs was determined in 10 cases. In total, 200 chromosomes were studied. Equal allele dosage was observed in 24 of 26 tetrasomies, and only 7 UPDs were found. These data strongly suggest that hyperdiploidy in childhood ALL generally arises by a simultaneous gain of all additional chromosomes in a single abnormal mitosis. © 2005 Wiley-Liss, Inc.
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