CRLF2 sequencing project Exomes
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ABSTRACT:
PROVIDER: EGAS00001000081 | EGA |
REPOSITORIES: EGA
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Project description:I hope to gain insight into novel genetic aberrations present in these patients that will highlight
important pathways that are involved in this subtype of leukaemia. It would be interesting to see if
the mutations and pathways that are activated are consistent between the patients, or differences
are observed dependent upon whether the patient has the translocation or the PAR1 deletion. Of
note is the high association with either numerical gains of chromosome X or numerical/structural
abnormalities of chromosome 21 (Down syndrome, iAMP21) in patients with CRLF2 deregulation. I
hope to find abnormalities linking chromosomes X and 21 to CRLF2 deregulation in BCP?ALL. By
including the three patients that are normal for CRLF2, but have consistent genetic abnormalities
found in the experimental cohort, I expect to find genetic differences between these two groups
that will help us to identify novel molecular targets specific to CRLF2 deregulation.
| EGAS00001000080 | EGA
Project description:Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) shown to have a dismal outcome on standard therapy. For improved diagnosis and prognosis of these patients, the initiating genetic events need to be elucidated. To investigate the genetic basis, the genomes of 94 iAMP21 patients were interrogated by genomic arrays, FISH and MLPA. Detailed mapping of chromosome 21 refined the common region of amplification (CRA) to 5.1 Mb; including the RUNX1 gene, miR-802 and genes mapping to the Down Syndrome Critical Region. Over a quarter of copy number alterations targeted chromosome 21, including telomeric deletions in 88% of patients. Global analysis by genomic arrays identified recurrent abnormalities affecting genes in key pathways. The frequency of these abnormalities were determined by FISH and/or MLPA; IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%) and RB1 (37%). Study of the clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 instability. This study provides convincing evidence that chromosome 21 instability is the only abnormality common to all iAMP21 patients and the initiating event is likely hidden within the complex structural rearrangements of this abnormal chromosome.
2012-03-02 | GSE26192 | GEO
Project description:Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) shown to have a dismal outcome on standard therapy. For improved diagnosis and prognosis of these patients, the initiating genetic events need to be elucidated. To investigate the genetic basis, the genomes of 94 iAMP21 patients were interrogated by genomic arrays, FISH and MLPA. Detailed mapping of chromosome 21 refined the common region of amplification (CRA) to 5.1 Mb; including the RUNX1 gene, miR-802 and genes mapping to the Down Syndrome Critical Region. Over a quarter of copy number alterations targeted chromosome 21, including telomeric deletions in 88% of patients. Global analysis by genomic arrays identified recurrent abnormalities affecting genes in key pathways. The frequency of these abnormalities were determined by FISH and/or MLPA; IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%) and RB1 (37%). Study of the clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 instability. This study provides convincing evidence that chromosome 21 instability is the only abnormality common to all iAMP21 patients and the initiating event is likely hidden within the complex structural rearrangements of this abnormal chromosome. DNA copy number analysis of 17 diagnostic and 1 relapse acute lymphoblastic leukaemia samples was performed using agilent 185K microarrays. These samples were hybridised against gender matched reference DNA.
2012-03-02 | E-GEOD-26192 | biostudies-arrayexpress
Project description:Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia We report two novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age 16 years), whilst the patients with the deletion were younger (median age 4 years). The two abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Over-expression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 over-expression in lymphoid transformation. In Down Syndrome (DS) ALL and two non DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain suggesting oncogenic cooperation, as well as highlighting a link between non DS ALL and JAK2 mutations. Keyword(s): Global copy number analysis using Agilent oligonucleotide arrays DNA copy number analysis of 16 acute lymphoblastic leukaemia samples (13 diagnostic, 1 diagnostic and relapse pair and 2 cell-lines) was performed using Agilent 244K and 105K custom microarrays. These samples were hybridised against gender matched reference DNA.
2010-05-16 | E-GEOD-17165 | biostudies-arrayexpress
Project description:Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia We report two novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age 16 years), whilst the patients with the deletion were younger (median age 4 years). The two abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Over-expression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 over-expression in lymphoid transformation. In Down Syndrome (DS) ALL and two non DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain suggesting oncogenic cooperation, as well as highlighting a link between non DS ALL and JAK2 mutations. Keyword(s): Global copy number analysis using Agilent oligonucleotide arrays
2009-07-18 | GSE17165 | GEO
Project description:Chromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences of somatic pairing have not been established. Gene expression profiling studies revealed that somatic pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the paired regions and resulted in the deregulation of the prolyl-hydroxylase EGLN2, a key protein that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of EGLN2 in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional changes that occur following DNA amplification. Therefore, in addition to numerical and structural chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma. Keywords: Gene expression profiling, SNP analysis, renal, tumor Oncocytoma and Chromophobe RCC samples - expression profiling and SNP chip analysis
2010-05-25 | E-GEOD-8271 | biostudies-arrayexpress
Project description:Chromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences of somatic pairing have not been established. Gene expression profiling studies revealed that somatic pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the paired regions and resulted in the deregulation of the prolyl-hydroxylase EGLN2, a key protein that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of EGLN2 in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional changes that occur following DNA amplification. Therefore, in addition to numerical and structural chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma. Keywords: Gene expression profiling, SNP analysis, renal, tumor
2008-08-13 | GSE8271 | GEO
Project description:Deregulated expression of the type I cytokine receptor, CRLF2 (CRLF2-d), is observed in 5-15% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), is associated with activation of the JAK/STAT pathway and has an inferior outcome compared to those with good risk cytogenetics. We aimed to determine the clinical and genetic landscape of CRLF2-d ALL using genomic approaches including karyotyping, fluorescence in situ hybridisation, whole genome and whole exome sequencing. The clinical and demographic features of CRLF2-d patients were characteristic of BCP-ALL. Patients with IGH-CRLF2 were older than those with P2RY8-CRLF2 (4yrs v 14yrs, p<0.001), while the incidence of CRLF2-d among Down syndrome patients was high (31%). CRLF2-d co-occurred with established primary chromosomal rearrangements but the majority (72%) had B-other ALL. The copy number alteration (CNA) profile was similar to B-other ALL, although CRLF2-d patients harboured higher frequencies of IKZF1 (43% v 23%) and BTG1 deletions (15% v 2%). There were differences in the CNA profile between IGH-CRLF2 and P2RY8-CRLF2 patients: deletions of IKZF1 (71% v 33% p<0.001), BTG1 (31% v 9%, p=0.004) and ADD3 (46% v 13%, p=0.008). A novel gene fusion, USP9X-DDX3X was discovered in 18% of CRLF2-d ALL. Pathway analysis of the mutational profile revealed novel involvement of the focal adhesion pathway. In conclusion, CRLF2-d defines a discrete subtype of B-other ALL, characterised by a distinctive profile of cooperating abnormalities, which drive leukaemogenesis in conjunction with CRLF2-d. Although the functional relevance of many of these abnormalities are unknown, they likely activate alternative pathways, which may represent novel therapeutic targets. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or remission bone marrow.
2017-02-24 | GSE83272 | GEO
Project description:Seventeen T-ALL patients out of 120 (14.2%) presented CRLF2 expression 5 times higher than the median (‘CRLF2-high’) with a significantly inferior 5-y EFS and an increased CIR compared to CRLF2-low patients.GEP of 15 T-ALL patients with (‘CRLF2-high’) were compared to 15 CRLF2-low patients. GSEA identified cell cycle deregulating gene sets.
2017-03-01 | GSE72623 | GEO
Project description:Background Children with Down Syndrome have an augmented risk for B-cell acute lymphoblastic leukaemia (DS-ALL), which is associated with a survival lower than in non-DS ALL, due to increased chemotherapy-related toxicity and a higher relapse rate, thus demanding new tailored therapeutic strategies. Cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while alterations in CRLF2 and IKZF1 genes are increased. Aim of the study was to evaluate in DS-ALL children the incidence and prognostic value of the Philadelphia Chromosome-Like (Ph-like) status and the “IKZF1plus” profile, both associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols for BCP-ALL. Method Seventy DS-ALL patients at diagnosis treated in Italian centres from 2000 to 2014 were evaluated for their cytogenetic status, including the Ph-like ALL profile, while the IKZF1plus feature was investigated in a larger cohort of 134 patients treated in Italian and German centres from 2000 to 2011. Findings Forty-six out of 70 (65•7%) AIEOP DS-ALL patients displayed the Ph-like ALL gene expression signature, mostly characterized by CRLF2 (n=33) and IKZF1 (n=16) alterations (13 had both alterations); only one case was positive for an ABL-class and one for a PAX5 fusion gene. In the Italian and German joint cohort, we observed 35•6% patients positive for P2RY8::CRLF2 fusion, 24•8% for IKZF1 deletion and 18% for IKZF1plus feature. Unexpectedly, a higher IKZF1 expression and activity were observed in IKZF1plus than IKZF1 wt DS-ALL patients. Ph-like signature and IKZF1 deletion were associated with poor outcome, which further worsens when IKZF1 deletion was co-occurring with P2RY8::CRLF2, qualifying for the IKZF1plus definition. Interpretation These subgroups, which for the most part are not associated with other high risk features, need new and tailored therapeutic strategies, not only focussed on the use of drugs that restore IKZF1 function.
2023-05-31 | GSE200864 | GEO