Gene expression signature of chronic lymphocytic leukaemia with Trisomy 12 (original) (raw)
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Low CD23 expression correlates with high CD38 expression and the presence of trisomy 12 in CLL
Hematological Oncology, 2015
Chronic lymphocytic leukemia (CLL) is characterized by a neoplastic B-cell population coexpressing CD5 and CD23; however, the expression of CD23 is variable. In human, two isotypes of CD23 have been identified and related to different functions. The aim of our study was to investigate the relative expression of the two CD23 isotypes in CLL and find possible correlation with other prognostic factors. The expression of CD23 isotypes was analyzed in 54 cases of CLL by polymerase chain reaction (PCR) and quantitative real-time PCR. The immunophenotype of CLL cells was characterized by flow cytometry. We demonstrated a higher CD23a than CD23b expression of CLL cells. Our results also revealed two subsets of CLL cases with a distinct CD23 isotype expression pattern. Thirty-two percent of the cases (group CLL1) showed both low mRNA level of CD23 isotypes and high protein levels of CD20 and CD38 in contrast to group CLL2 with high CD23 mRNA levels. By correlating these results to the presence of prognostic factors determined by fluorescence in situ hybridization, we found that the majority of the cases of group CLL1 (14/17) carried trisomy 12. In summary, our results confirm a high CD23a/CD23b ratio of the CLL cells and demonstrate that in a subset of CLL cases, low CD23 expression together with high CD20 and CD38 expressions may serve as a surrogate for trisomy 12.
Hematological Oncology, 2015
The prognosis of chronic lymphocytic leukemia (CLL) patients displaying trisomy 12 (+12) remains unclear. In this study, we analyzed the influence of the proportion of cells with +12, and other clinical and biologic factors, in time to first therapy (TTFT) and overall survival (OS), in 289 patients diagnosed with CLL carrying +12. Median OS was 129 months. One hundred seventy-four patients (60.2%) presented +12 in <60% of cells. TTFT and OS for this subgroup were longer than for the subgroup with +12 in ≥60% of cells, with a median TTFT of 49 months (CI95%, 39-58) vs 30 months (CI95%, 22-38) (P = 0.001); and a median OS of 159 months (CI95%, 119-182), vs 96 months (CI95%, 58-134) (P = 0.015). Other factors associated with a shorter TTFT were: Binet stage, B symptoms, lymphadenopathy, splenomegaly, high lymphocyte count, 11q-, high β 2 microglobulin, and high LDH. In the multivariate analysis, clinical stage, +12 in ≥60% of cells, high lymphocyte count, B symptoms, and 11q-in addition, resulted of significance in predicting shorter TTFT. Significant variables for OS were: Binet stage, lymphadenopathy, splenomegaly, high LDH, high β 2 microglobulin, 11q-, and CD38. In the multivariate analysis, only Binet stage, 11q-, and high β2microglobulin significantly predicted shorter OS. CLL with +12 entails a heterogeneous group with intermediate prognosis. However, a high proportion of cells carrying +12 separates a subgroup of patients with poor outcome. . a) Kaplan-Meier curve for time to first therapy (TTFT) in 289 patients with +12 and percentage of +12(< vs ≥60%) (A); (P < 0.005; log-rank test). b) Kaplan-Meier curve for time to first therapy (TTFT) in 289 patients with +12 and Binet stage (B) (P < 0.005; log-rank test). c) Kaplan-Meier curve for time to first therapy (TTFT) in 289 patients with +12 and B symptoms (P < 0.005; log-rank test). d) Kaplan-Meier curve for time to first therapy (TTFT) in 289 patients with +12 and lymphadenopathy (D) (P < 0.005; log-rank test). e) Kaplan-Meier curve for time to first therapy (TTFT) in 289 patients with +12 and splenomegaly (E) (P < 0.005; log-rank test). f) Kaplan-Meier curves for time to first therapy (TTFT) in 289 patients with +12 and lymphocyte count (F) (P < 0.005; log-rank test). g) Kaplan-Meier curve for time to first therapy (TTFT) in 289 patients with +12 and LDH (G) (P < 0.005; log-rank test). h) Kaplan-Meier curve for time to first therapy (TTFT) in 289 patients with +12 and β 2 microglobulin (B2M) (H) (P < 0.005; log-rank test) Worse prognosis in CLL patients with a high number +12 cells
Trisomy 12 is uncommon in typical chronic lymphocytic leukaemias
British Journal of Haematology, 1994
The incidence of trisomy 12 was studied by conventional chromosome analysis in 11 1 patients referred as B-cell chronic lymphocytic leukaemia (B-CLL). Fluorescent in situ hybridization (FISH) was also applied in 34 of those patients with either a normal karyotype or no analysable mitoses. By karyotyping, trisomy 12 was present in 11'7% (1 3/111), whereas additional FISH increased the incidence to 14.4% (16/111). When subdividing our cases in either typical CLL (n = go), fulfilling the FAB classification criteria, or atypical CLL (n = 21). with one or more variations from those criteria, the incidence of t 1 2 by metaphase analysis was 3% and 48%. respectively. Additional FISH increased the incidence to 4% and 57%. The most common aberration in atypical CLL was FMC7 positivity (n = 11). followed by CD5 negativity (n = 8), strong surface immunoglobulin staining (n = 7 ) and atypical morphology (n = 6). Trisomy 12 could only be demonstrated in a small proportion of neoplastic cells in all positive cases. By FISH and/or karyotyping, all available samples at diagnosis of the disease were positive.
Identification of a gene on chromosome 12q22 uniquely overexpressed in chronic lymphocytic leukemia
2006
The pathogenesis of chronic lymphocytic leukemia (CLL) is unknown but may in- volve aberrant activation of signaling pathways. Somatic hypermutations in re- arranged immunoglobulin heavy-chain (IgVH) genes allow a division of CLL pa- tients into 2 categories: mutated IgVH genes are associated with an indolent disease, whereas unmutated IgVH genes define an aggressive form. Using differen- tial display to compare
Co-existence of t(6;13)(p21;q14.1) and trisomy 12 in chronic lymphocytic leukemia
Medical Oncology
We report a case of a 57-year-old man diagnosed with chronic lymphocytic leukemia (CLL) and presence of a rare t(6;13)(p21;q14.1) in association with an extra copy of chromosome 12. Classical cytogenetic analysis using the immunostimulatory combination of DSP30 and IL-2 showed the karyotype 47,XY,t(6;13)(p21;q14.1), +12 in 75% of the metaphase cells. Spectral karyotype analysis (SKY) confirmed the abnormality previously seen by G-banding. Additionally, interphase fluorescence in situ hybridization using an LSI CEP 12 probe performed on peripheral blood cells without any stimulant agent showed trisomy of chromosome 12 in 67% of analyzed cells (134/200). To the best of our knowledge, the association of t(6;13)(p21;q14.1) and +12 in CLL has never been described. The prognostic significance of these new findings in CLL remains to be elucidated. However, the patient has been followed up since 2009 without any therapeutic intervention and has so far remained stable.
Molecular Cytogenetics, 2016
Background: Deletion of 13q14 is the most common cytogenetic change in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is detected in about 50 % of patients by fluorescence in situ hybridization (FISH), which can reveal presence of del(13)(q14) and mono-or biallelic deletion status without information about the size of the lost region. Array-comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) can detect submicroscopic copy number changes, loss of heterozygosity (LOH) and uniparental disomy (UPD) regions. The purpose of this study was detection of the size of del(13)(q14) deletion in our group of patients, comparing the size of the monoallelic and biallelic deletions, detection of LOH and UPD regions. Results: We have investigated 40 CLL/SLL patients by karyotype, FISH and CGH and SNP array. Mutational status was of immunoglobulin heavy-chain variable-region (IGVH) was also examined. The size of deletion ranged from 348,12 Kb to 38.97 Mb. Detected minimal deleted region comprised genes: TRIM13, miR-3613, KCNRG, DLEU2, miR-16-1, miR-15a, DLEU1. The RB1 deletions were detected in 41 % of cases. The average size in monoallelic 13q14 deletion group was 7,2 Mb while in biallelic group was 4,8 Mb. In two cases 13q14 deletions were located in the bigger UPD regions. Conclusions: Our results indicate that bigger deletion including RB1 or presence of biallelic 13q14 deletion is not sufficient to be considered as adverse prognostic factor in CLL/SLL. CytoSure Haematological Cancer and SNP array (8x60k) can precisely detect recurrent copy number changes with known prognostic significance in CLL/SLL as well as other chromosomal imbalances. The big advantage of this array is simultaneous detection of LOH and UPD regions during the same test.
1993
Fluorescence in situ hybridization (FISH) with a chromo- some 12 specific a-centromeric probe was performed on interphase cells from 183 patients with B-cell chronic lym- phocytic leukemia (CLL). Twenty one cases with trisomy 12 (1 1.5%) were detected. The number of trisomic cells ranged from 5.5% to 76% (mean 38.5%). No correlation was found between the presence of trisomy 12 and white blood cell count, hemoglobin level, platelet count, a spe- cific immunophenotype, clinical stage, sex, splenomegaly, or lymphadenopathy. Morphologic review of all cases with trisomy 12 showed seven (33%) with more than 10% pro- lymphocytes and three (1 4%) with CLL of mixed cell type. While trisomy 12 is the most common chromosomal ab- -CELL CHRONIC lymphocytic leukemia (CLL) re- B sults from the clonal expansion of mature looking lymphocytes.' A degree of morphologic heterogeneity has been recognized for a number of years223; recently, this has been examined by the French-American-British (FAB)...