RNA-based markers as prognostic factors in chronic lymphocytic leukemia

Sevov, Marie; Rosenquist, Richard; Mansouri, Larry

doi:10.1586/ehm.11.80

Cited by 10 publications

(9 citation statements)

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“…It brought great advances in cancer research and disclosed deregulated transcripts that are now being considered as prognostic or therapeutic biomarkers of neoplastic diseases (Sevov et al, 2012;Campo, 2013). Considering the availability of novel therapeutic possibilities for rare muscle disorders (Aartsma-Rus and Muntoni, 2013), finding prognostic biomarkers for disease severity or drug response will be of great benefit for patient care and treatment (Ferlini et al, 2013;Scotton et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy

Scotton

Bovolenta

Schwartz

et al. 2016

Journal of Cell Science

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Collagen VI myopathies are genetic disorders caused by mutations in collagen 6 A1, A2 and A3 genes, ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, which is recapitulated by collagen-VI-null (Col6a1 −/− ) mice. Abnormalities in mitochondria and autophagic pathway have been proposed as pathogenic causes of collagen VI myopathies, but the link between collagen VI defects and these metabolic circuits remains unknown. To unravel the expression profiling perturbation in muscles with collagen VI myopathies, we performed a deep RNA profiling in both Col6a1 −/− mice and patients with collagen VI pathology. The interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1 −/− (also known as Arntl) mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and of autophagy-related genes. The involvement of circadian rhythms in collagen VI myopathies is new and links autophagy and mitochondrial abnormalities. It also opens new avenues for therapies of hereditary myopathies to modulate the molecular clock or potential gene-environment interactions that might modify muscle damage pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy

Scotton

Bovolenta

Schwartz

et al. 2016

Journal of Cell Science

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“…Chronic lymphocytic leukemia (CLL), a heterogeneous disease with a variable outcome, can be subdivided into clinically relevant subgroups based on molecular, cytogenetic, and phenotypic features and a large set of potential prognostic biomarkers have been identified (reviewed in [4][5][6]). The future status of these biomarkers as a basis for clinical decision makings has not yet been fully defined, although the immunoglobulin heavy chain variable (IGHV) gene mutational status and in particular the presence of certain recurrent genomic aberrations (i.e., 11q2, 112, 13q2, 17p2) are commonly applied biomarkers [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…In general, malignant cells have shorter telomeres than their normal counterparts and there is an association between short telomeres and acquisition of genetic aberrations, risk of transformation and tumor progression [1][2][3]. Hence, TL as a potential clinical biomarker in cancer has gained considerable interest and its importance in hematological malignancies has been broadly investigated.Chronic lymphocytic leukemia (CLL), a heterogeneous disease with a variable outcome, can be subdivided into clinically relevant subgroups based on molecular, cytogenetic, and phenotypic features and a large set of potential prognostic biomarkers have been identified (reviewed in [4][5][6]). The future status of these biomarkers as a basis for clinical decision makings has not yet been fully defined, although the immunoglobulin heavy chain variable (IGHV) gene mutational status and in particular the presence of certain recurrent genomic aberrations (i.e., 11q2, 112, 13q2, 17p2) are commonly applied biomarkers [5][6][7].…”

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Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

et al. 2013

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Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n 5 265) and in relation to other prognostic markers. Short telomeres were particularly associated with high-risk genetic markers, such as NOTCH1, SF3B1, or TP53 aberrations, and predicted a short time to treatment (TTT) and overall survival (OS) (both P < 0.0001). TL was an independent prognostic factor and subdivided patients with otherwise good-prognostic features (e.g., mutated IGHV genes, favorable cytogenetics) into subgroups with different outcome. Furthermore, in follow-up samples (n 5 119) taken 5-8 years after diagnosis, TL correlated well with TL at diagnosis and remained unaffected by treatment. Altogether, these novel data indicate that short TL already at diagnosis is associated with poor outcome in CLL and that TL can be measured at later stages of the disease. Am. J. Hematol. 88:647-651, 2013. V C 2013 Wiley Periodicals, Inc. IntroductionTelomeres are specialized structures at chromosome ends which serve to protect these ends from being recognized as DNA double-strand breaks. In addition, the repetitive telomere sequences serve as a buffer of non-gene coding DNA when the telomere ends shorten due to the "end replication problem." Telomere maintenance and integrity in hematopoietic cells is executed by telomerase adding new telomeric repeats to the ends in collaboration with telomere length regulators, i.e., the shelterins. The net result of these acting forces defines the actual cellular TL which can serve as a biomarker for telomere integrity and dysfunction. There is growing evidence that TL carries information of clinical importance for cancer patients. In general, malignant cells have shorter telomeres than their normal counterparts and there is an association between short telomeres and acquisition of genetic aberrations, risk of transformation and tumor progression [1][2][3]. Hence, TL as a potential clinical biomarker in cancer has gained considerable interest and its importance in hematological malignancies has been broadly investigated.Chronic lymphocytic leukemia (CLL), a heterogeneous disease with a variable outcome, can be subdivided into clinically relevant subgroups based on molecular, cytogenetic, and phenotypic features and a large set of potential prognostic biomarkers have been identified (reviewed in [4][5][6]). The future status of these biomarkers as a basis for clinical decision makings has not yet been fully defined, although the immunoglobulin heavy chain variable (IGHV) gene mutational status and in particular the presence of certain recurrent genomic aberrations (i.e., 11q2, 112, 13q2, 17p2) are commonly applied biomarkers [5][6][7]. Several studies have lately indicated TL as a potential prognostic marker in CLL, whereby short telomeres may predict poor clinical outcome [8][9][10][11][12][13][14][15]. Furthermore, a stro...

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“…[9][10][11] In particular, the expression of genes such as CLLU1, ADAM29 and LPL have recently been associated with different outcomes in CLL. [12][13][14][15][16][17] CLLU1 located at chromosome 12q22, encodes a novel transcript, which has been identified as a marker specific to CLL. 18 In particular, high CLLU1 expression (CLLU1-H) is significantly more frequent in unmutated IGHV and CD38 + CLL.…”

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CLLU1 expression has prognostic value in chronic lymphocytic leukemia after first-line therapy in younger patients and in those with mutated IGHV genes

et al. 2012

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Articles Chronic Lymphocytic Leukemia 274haematologica | 2013; 98(2) IntroductionChronic lymphocytic leukemia (CLL) is a heterogeneous disease with a highly variable outcome depending on clinical and biological characteristics. Clinical staging is a relatively simple method of assessing the outcome of CLL patients based on clinical parameters.1,2 In the last two decades, multiple biological markers have been shown to have prognostic relevance in CLL, most notably chromosomal aberrations, IGHV mutations and expression of surface markers such as ZAP-70 and CD38. [3][4][5][6][7][8] Gene expression analyses have also revealed the heterogeneity of CLL, with distinct gene expression signatures being associated with particular genetic subgroups of CLL. [9][10][11] In particular, the expression of genes such as CLLU1, ADAM29 and LPL have recently been associated with different outcomes in CLL. [12][13][14][15][16][17] CLLU1 located at chromosome 12q22, encodes a novel transcript, which has been identified as a marker specific to CLL. 18 In particular, high CLLU1 expression (CLLU1-H) is significantly more frequent in unmutated IGHV and CD38 + CLL. 19,20 CLLU1-H has been shown to be associated with shorter overall survival and shorter time to first treatment in patients with early stage CLL, 20 especially those younger than 70 years. 13 In addition, CLLU1 expression has been shown to be a specific and stable marker in CLL cells, 21 making it a promising marker not only for prognosis but also for minimal residual disease analysis. 22 However, the effect of CLLU1 expression on response to therapy is currently unknown and, to date, there are no data on the significance of CLLU1 expression with regards to progression-free survival and overall survival in patients receiving first-line therapy. We assessed the value of CLLU1 expression as a prognostic marker in the LRF CLL4 randomized controlled trial. Design and Methods Patients and samplesPre-treatment blood samples were collected at the time of entry into the trial and were available for CLLU1 expression analysis from 515 of the 777 patients. The patients were previously untreated, 25% having Binet stage A-progressive disease, 45% stage B and 30% stage C. The male:female ratio was 3:1 and the median age was 65 years (range, 35-86 years). Patients were randomized to receive chlorambucil, fludarabine, or fludarabine with cyclophosphamide. The trial was approved by a multicenter research ethics committee and all patients gave informed consent. RNA extraction and CLLU1 expression analysisRNA was extracted using the RNeasy Mini Kit (Qiagen) after which ©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.070201 DG and ME contributed CLLU1, located at chromosome 12q22, encodes a transcript specific to chronic lymphocytic leukemia and has potential prognostic value. We assessed the value of CLLU1 expression in the LRF CLL4 randomized trial. Samples from 515 patients with chronic lymphocytic leukemia were collected immediately before the start ...

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RNA-based markers as prognostic factors in chronic lymphocytic leukemia

Cited by 10 publications

References 113 publications

Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy

Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy

Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

CLLU1 expression has prognostic value in chronic lymphocytic leukemia after first-line therapy in younger patients and in those with mutated IGHV genes

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