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Are submicroscopic chromosomal inversions predisposing factors for the t(9;22)(q34;q11.2) translocation in chronic myeloid leukemia?

ABSTRACT: A complex chromosomal rearrangement observed in a patient with chronic myeloid leukemia was explained as the consequence of a multistep process. The explanation involved an initial t(9;22) translocation with breakpoints distant from the BCR and ABL1 genes followed by genomic deletions that produced the BCR-ABL1 hybrid gene. We present an alternative model that fits the origin of the patient's rearrangement better. The present model links submicroscopic inversions with the occurrence of the t(9;22) translocation and opens a new approach on the research on the disease.

SUBMITTER: Gonzalez Garcia JR

PROVIDER: S-EPMC4348163 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Are submicroscopic chromosomal inversions predisposing factors for the t(9;22)(q34;q11.2) translocation in chronic myeloid leukemia?

González García Juan Ramón JR Cruz Martín Daniel Domínguez MD Gutiérrez César Borjas CB

Molecular cytogenetics 20150222

A complex chromosomal rearrangement observed in a patient with chronic myeloid leukemia was explained as the consequence of a multistep process. The explanation involved an initial t(9;22) translocation with breakpoints distant from the BCR and ABL1 genes followed by genomic deletions that produced the BCR-ABL1 hybrid gene. We present an alternative model that fits the origin of the patient's rearrangement better. The present model links submicroscopic inversions with the occurrence of the t(9;2 ...[more]

PMID: 25741382

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Variant Philadelphia t(X;9;22)(q22?;q34;q11.2) can be successfully treated with second generation tyrosine kinase inhibitors: A case report and literature review.

Project description:Chronic myeloid leukemia (CML) is characterized by the reciprocal translocation between chromosomes 9 and 22: t(9;22)(q34;q11). However, 5-10% of patients with CML have complex variant translocations involving at least a third chromosome; only a few cases affect the X chromosome. Therefore, the data available regarding their features and the response to treatment is limited. In the present report, a case of a variant Philadelphia translocation t(X;9;22)(q22?;q34;q11.2) identified in a 51-year-old female with a newly diagnosed CML is described. The patient was treated with nilotinib. A major molecular response was observed after 12 months of starting treatment. Deep molecular response was obtained 20 months later and maintained after the 110-month follow-up. Additionally, a literature review was performed, with the aim of comprehending the complex clinical and biological characteristics of CML cytogenetic variants involving the X chromosome.

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The t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia activates the BHLHB1 gene.

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Gene expression profiling of chronic myeloid leukemia with variant t(9;22) reveals a different signature from cases with classic translocation.

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Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation.

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Non random distribution of genomic features in breakpoint regions involved in chronic myeloid leukemia cases with variant t(9;22) or additional chromosomal rearrangements.

Project description:BackgroundThe t(9;22)(q34;q11), generating the Philadelphia (Ph) chromosome, is found in more than 90% of patients with chronic myeloid leukemia (CML). As a result of the translocation, the 3' portion of the ABL1 oncogene is transposed from 9q34 to the 5' portion of the BCR gene on chromosome 22 to form the BCR/ABL1 fusion gene. At diagnosis, in 5-10% of CML patients the Ph chromosome is derived from variant translocations other than the standard t(9;22).ResultsWe report a molecular cytogenetic study of 452 consecutive CML patients at diagnosis, that revealed 50 cases identifying three main subgroups: i) cases with variant chromosomal rearrangements other than the classic t(9;22)(q34;q11) (9.5%); ii) cases with cryptic insertions of ABL1 into BCR, or vice versa (1.3%); iii) cases bearing additional chromosomal rearrangements concomitant to the t(9;22) (1.1%). For each cytogenetic group, the mechanism at the basis of the rearrangement is discussed.All breakpoints on other chromosomes involved in variant t(9;22) and in additional rearrangements have been characterized for the first time by Fluorescence In Situ Hybridization (FISH) experiments and bioinformatic analyses. This study revealed a high content of Alu repeats, genes density, GC frequency, and miRNAs in the great majority of the analyzed breakpoints.ConclusionsTaken together with literature data about CML with variant t(9;22), our findings identified several new cytogenetic breakpoints as hotspots for recombination, demonstrating that the involvement of chromosomes other than 9 and 22 is not a random event but could depend on specific genomic features. The presence of several genes and/or miRNAs at the identified breakpoints suggests their potential involvement in the CML pathogenesis.

| S-EPMC2887383 | biostudies-literature

t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients.

Project description:Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature.

| S-EPMC4008104 | biostudies-literature

Gene expression profiling of chronic myeloid leukemia with variant t(9;22) reveals a different signature from cases with classic translocation.

Project description:The t(9;22)(q34;q11) generating the Philadelphia chromosome and the BCR/ABL1 fusion gene represents the cytogenetic hallmark of chronic myeloid leukemia (CML). About 5–10% of CML cases show variant translocations with the involvement of other chromosomes in addition to chromosomes 9 and 22. The molecular bases of differences between CML patients with classic and variant t(9;22) have never been elucidated. In this study, we performed gene expression microarrays analysis to compare CML patients bearing variant rearrangements and those with classic t(9;22)(q34;q11). We identified a list of 59 differentially expressed genes significantly associated with the two analyzed groups. These genes are mostly involved in the intracellular protein kinase cascade and their upregulation enhances cellular processes already known to sustain the CML pathogenesis.

2013-10-01 | GSE41375 | GEO

Gene expression profiling of chronic myeloid leukemia with variant t(9;22) reveals a different signature from cases with classic translocation.

Project description:The t(9;22)(q34;q11) generating the Philadelphia chromosome and the BCR/ABL1 fusion gene represents the cytogenetic hallmark of chronic myeloid leukemia (CML). About 5M-bM-^@M-^S10% of CML cases show variant translocations with the involvement of other chromosomes in addition to chromosomes 9 and 22. The molecular bases of differences between CML patients with classic and variant t(9;22) have never been elucidated. In this study, we performed gene expression microarrays analysis to compare CML patients bearing variant rearrangements and those with classic t(9;22)(q34;q11). We identified a list of 59 differentially expressed genes significantly associated with the two analyzed groups. These genes are mostly involved in the intracellular protein kinase cascade and their upregulation enhances cellular processes already known to sustain the CML pathogenesis. According to conventional and molecular cytogenetics (FISH) data, 12 CML cases with classic t(9;22) and of 8 cases with variant translocations were selected and analyzed by GEP.

2013-10-01 | E-GEOD-41375 | biostudies-arrayexpress

Submicroscopic chromosomal imbalances contribute to early abortion.

Project description:BackgroundChromosomal abnormalities are one of the genetic mechanisms associated with abortion. However, the roles of submicroscopic chromosomal imbalances in early abortion are still unclear. This study aims to find out whether submicroscopic chromosomal imbalances contribute to early abortion.MethodsA total of 78 chorionic villus specimens from early spontaneous abortion patients with no obvious abnormality are collected after miccroassay analysis (the case group). At the same time, 60 chorionic villus specimens from induced abortion patients with no obvious abnormality are selected as the control group. The submicroscopic structures of chromosomes from two groups are analyzed using an array-based comparative genomic hybridization (aCGH).ResultsIn the case group, 15 specimens show submicroscopic chromosomal abnormalities including 14 micro-deletion/micro-duplication in chromosomes 2, 4, 5, 6, 7, 8, 9, 12, 15, 16, 18, and 22, and 1 uniparental disomy (UPD) in chromosome 19. Moreover, no pathogenic copy number variations are found in the control group. The results between these two groups exhibit significantly statistical difference.ConclusionSubmicroscopic chromosomal imbalances may be one of the main reasons for early abortion.

| S-EPMC6054741 | biostudies-literature

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