Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group study.
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ABSTRACT:
SUBMITTER: Chen IM
PROVIDER: S-EPMC3325039 | biostudies-literature | 2012 Apr
REPOSITORIES: biostudies-literature
Publications
Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group study.
Chen I-Ming IM Harvey Richard C RC Mullighan Charles G CG Gastier-Foster Julie J Wharton Walker W Kang Huining H Borowitz Michael J MJ Camitta Bruce M BM Carroll Andrew J AJ Devidas Meenakshi M Pullen D Jeanette DJ Payne-Turner Debbie D Tasian Sarah K SK Reshmi Shalini S Cottrell Catherine E CE Reaman Gregory H GH Bowman W Paul WP Carroll William L WL Loh Mignon L ML Winick Naomi J NJ Hunger Stephen P SP Willman Cheryl L CL
Blood 20120224 15
As controversy exists regarding the prognostic significance of genomic rearrangements of CRLF2 in pediatric B-precursor acute lymphoblastic leukemia (ALL) classified as standard/intermediate-risk (SR) or high-risk (HR), we assessed the prognostic significance of CRLF2 mRNA expression, CRLF2 genomic lesions (IGH@-CRLF2, P2RY8-CRLF2, CRLF2 F232C), deletion/mutation in genes frequently associated with high CRLF2 expression (IKZF1, JAK, IL7R), and minimal residual disease (MRD) in 1061 pediatric ALL ...[more]
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Project description:Gene expression profiling of 207 uniformly treated children with high-risk B-progenitor acute lymphoblastic leukemia revealed 29 of 207 cases (14%) with markedly elevated expression of CRLF2 (cytokine receptor-like factor 2). Each of the 29 cases harbored a genomic rearrangement of CRLF2: 18 of 29 (62%) had a translocation of the immunoglobulin heavy chain gene IGH@ on 14q32 to CRLF2 in the pseudoautosomal region 1 of Xp22.3/Yp11.3, whereas 10 (34%) cases had a 320-kb interstitial deletion centromeric of CRLF2, resulting in a P2RY8-CRLF2 fusion. One case had both IGH@-CRLF2 and P2RY8-CRLF2, and another had a novel CRLF2 rearrangement. Only 2 of 29 cases were Down syndrome. CRLF2 rearrangements were significantly associated with activating mutations of JAK1 or JAK2, deletion or mutation of IKZF1, and Hispanic/Latino ethnicity (Fisher exact test, P < .001 for each). Within this cohort, patients with CRLF2 rearrangements had extremely poor treatment outcomes compared with those without CRLF2 rearrangements (35.3% vs 71.3% relapse-free survival at 4 years; P < .001). Together, these observations suggest that activation of CRLF2 expression, mutation of JAK kinases, and alterations of IKZF1 cooperate to promote B-cell leukemogenesis and identify these pathways as important therapeutic targets in this disease.
| S-EPMC2902132 | biostudies-literature
Project description:Overexpression of cytokine receptor-like factor 2 (CRLF2) due to chromosomal rearrangement has been observed in acute lymphoblastic leukemia (ALL) and reported to contribute to oncogenesis and unfavorable outcome in ALL. We studied B-ALL and T-ALL patients without CRLF2 rearrangement and observed that CRLF2 is significantly increased in a subset of these patients. Our study shows that high CRLF2expression correlates with high-risk ALL markers, as well as poor survival. We found that the IKZF1-encoded protein, Ikaros, directly binds to the CRLF2 promoter and regulates CRLF2 expression in leukemia cells. CK2 inhibitor, which can increase Ikaros activity, significantly increases Ikaros binding in ALL cells and suppresses CRLF2 expression in an Ikaros-dependent manner. CRLF2 expression is significantly higher in patients with IKZF1 deletion as compared to patients without IKZF1 deletion. Treatment with CK2 inhibitor also results in an increase in IKZF1 binding to the CRLF2 promoter and suppression of CRLF2 expression in primary ALL cells. We further observed that CK2 inhibitor induces increased H3K9me3 histone modifications in the CRLF2 promoter in ALL cell lines and primary cells. Taken together, our results demonstrate that high expression of CRLF2 correlates with high-risk ALL and short survival in patients without CRLF2 rearrangement. Our results are the first to demonstrate that the IKZF1-encoded Ikaros protein directly suppresses CRLF2 expression through enrichment of H3K9me3 in its promoter region. Our data also suggest that high CRLF2 expression works with the IKZF1 deletion to drive oncogenesis of ALL and has significance in an integrated prognostic model for adult high-risk ALL.
| S-EPMC5226542 | biostudies-literature
Project description:Minimal residual disease (MRD) as a marker of antileukemic drug efficacy is being used to assess risk status and, in some cases, to adjust the intensity of therapy. Within known prognostic categories, the determinants of MRD are not known. We measured MRD by flow cytometry at day 8 (in blood) and at day 28 (in bone marrow) of induction therapy in more than 1000 children enrolled in Pediatric Oncology Group therapy protocols 9904, 9905, and 9906. We classified patients as "best risk" if they had cleared MRD by day 8 of therapy and as "worst risk" if they had MRD remaining in bone marrow at day 28, and tested whether MRD was related to polymorphisms in 16 loci in genes hypothesized to influence response to therapy in acute lymphoblastic leukemia (ALL). After adjusting for known prognostic features such as presence of the TEL-AML1 rearrangement, National Cancer Institute (NCI) risk status, ploidy, and race, the G allele of a common polymorphism in chemokine receptor 5 (CCR5) was associated with more favorable MRD status than the A allele (P = .009, logistic regression), when comparing "best" and "worst" risk groups. These data are consistent with growing evidence that both acquired and host genetics influence response to cancer therapy.
| S-EPMC2265447 | biostudies-literature
Project description:ImportanceMinimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Assessing the association of MRD status following induction therapy in patients with acute lymphoblastic leukemia (ALL) with relapse and mortality may improve the efficiency of clinical trials and accelerate drug development.ObjectiveTo quantify the relationships between event-free survival (EFS) and overall survival (OS) with MRD status in pediatric and adult ALL using publications of clinical trials and other databases.Data sourcesClinical studies in ALL identified via searches of PubMed, MEDLINE, and clinicaltrials.gov.Study selectionOur search and study screening process adhered to the PRISMA Guidelines. Studies that addressed EFS or OS by MRD status in patients with ALL were included; reviews, abstracts, and studies with fewer than 30 patients or insufficient MRD description were excluded.Data extraction and synthesisStudy sample size, patient age, follow-up time, timing of MRD assessment (postinduction or consolidation), MRD detection method, phenotype/genotype (B cell, T cell, Philadelphia chromosome), and EFS and OS. Searches of PubMed and MEDLINE identified 566 articles. A parallel search on clinicaltrials.gov found 67 closed trials and 62 open trials as of 2014. Merging results of 2 independent searches and applying exclusions gave 39 publications in 3 arms of patient populations (adult, pediatric, and mixed). We performed separate meta-analyses for each of these 3 subpopulations.ResultsThe 39 publications comprised 13?637 patients: 16 adult studies (2076 patients), 20 pediatric (11?249 patients), and 3 mixed (312 patients). The EFS hazard ratio (HR) for achieving MRD negativity is 0.23 (95% Bayesian credible interval [BCI] 0.18-0.28) for pediatric patients and 0.28 (95% BCI, 0.24-0.33) for adults. The respective HRs in OS are 0.28 (95% BCI, 0.19-0.41) and 0.28 (95% BCI, 0.20-0.39). The effect was similar across all subgroups and covariates.Conclusions and relevanceThe value of having achieved MRD negativity is substantial in both pediatric and adult patients with ALL. These results are consistent across therapies, methods of and times of MRD assessment, cutoff levels, and disease subtypes. Minimal residual disease status warrants consideration as an early measure of disease response for evaluating new therapies, improving the efficiency of clinical trials, accelerating drug development, and for regulatory approval. A caveat is that an accelerated approval of a particular new drug using an intermediate end point, such as MRD, would require confirmation using traditional efficacy end points.
| S-EPMC5824235 | biostudies-literature
Project description:PurposeWhile the role of minimal residual disease (MRD) assessment and the significance of achieving an MRD-negative status during treatment have been evaluated in previous studies, there is limited evidence on the significance of MRD re-emergence without morphological relapse in acute lymphoblastic leukemia (ALL). We sought to determine the clinical significance of MRD re-emergence in pediatric ALL patients.MethodsBetween 2005 and 2017, this study recruited 1126 consecutive patients newly diagnosed with ALL. Flow cytometry was performed to monitor MRD occurrence during treatment.ResultsOf 1030 patients with MRD-negative results, 150 (14.6%) showed MRD re-emergence while still on morphological complete remission (CR). Patients with white blood cell counts of ≥50 × 109/L (p = 0.033) and MRD levels of ≥0.1% on day 33 (p = 0.012) tended to experience MRD re-emergence. The median re-emergent MRD level was 0.12% (range, 0.01-10.00%), and the median time to MRD re-emergence was 11 months (range, <1-52 months). Eighty-five (56.6%) patients subsequently developed relapse after a median of 4.1 months from detection of MRD re-emergence. The median re-emergent MRD level was significantly higher in the relapsed cohort than in the cohort with persistent CR (1.05% vs. 0.48%, p = 0.005). Of the 150 patients, 113 continued to receive chemotherapy and 37 underwent transplantation. The transplantation group demonstrated a significantly higher 2-year overall survival (88.7 ± 5.3% vs. 46.3 ± 4.8%, p < 0.001) and cumulative incidence of relapse (23.3 ± 7.4% vs. 64.0 ± 4.6%, p < 0.001) than the chemotherapy group.ConclusionsMRD re-emergence during treatment was associated with an adverse outcome in pediatric ALL patients. Transplantation could result in a significant survival advantage for these patients.
| S-EPMC7892594 | biostudies-literature
Project description:Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Institute high-risk (NCI HR) patients who were MRD(+). The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.
| S-EPMC2424148 | biostudies-literature
Project description:BackgroundContinuous complete clinical remission in T-cell acute lymphoblastic leukemia (T-ALL) is now approaching 80% due to the implementation of aggressive chemotherapy protocols but patients that relapse continue to have a poor prognosis. Such patients could benefit from augmented therapy if their clinical outcome could be more accurately predicted at the time of diagnosis. Gene expression profiling offers the potential to identify additional prognostic markers but has had limited success in generating robust signatures that predict outcome across multiple patient cohorts. This study aimed to identify robust gene classifiers that could be used for the accurate prediction of relapse in independent cohorts and across different experimental platforms.ResultsUsing HG-U133Plus2 microarrays we modeled a five-gene classifier (5-GC) that accurately predicted clinical outcome in a cohort of 50 T-ALL patients. The 5-GC was further tested against three independent cohorts of T-ALL patients, using either qRT-PCR or microarray gene expression, and could predict patients with significantly adverse clinical outcome in each. The 5-GC featured the interleukin-7 receptor (IL-7R), low-expression of which was independently predictive of relapse in T-ALL patients. In T-ALL cell lines, low IL-7R expression was correlated with diminished growth response to IL-7 and enhanced glucocorticoid resistance. Analysis of biological pathways identified the NF-kappaB and Wnt pathways, and the cell adhesion receptor family (particularly integrins) as being predictive of relapse. Outcome modeling using genes from these pathways identified patients with significantly worse relapse-free survival in each T-ALL cohort.ConclusionsWe have used two different approaches to identify, for the first time, robust gene signatures that can successfully discriminate relapse and CCR patients at the time of diagnosis across multiple patient cohorts and platforms. Such genes and pathways represent markers for improved patient risk stratification and potential targets for novel T-ALL therapies.
| S-EPMC2879253 | biostudies-literature
Project description:Interactions between common germline variants in ARID5B and IKZF1 and other known childhood acute lymphoblastic leukemia (ALL) risk factors were queried using biospecimens and data from 770 ALL cases and 384 controls. Case-control comparisons revealed dose-dependent associations between ARID5B rs10821936, ARID5B rs10994982, and IKZF1 rs11978267 and childhood ALL overall, and B lineage and B lineage hyperdiploid ALL examined separately (all allelic odds ratios ?1.33, Ptrend?0.001). No heterogeneity was observed between ORs for males and females (all Pinteraction?0.48). Likewise, no significant genotype-birth weight interactions were detected (all Pinteraction?0.12) among cases. These results indicate similar ALL risk across strata of known risk factors.
| S-EPMC3731070 | biostudies-literature
Project description:PAPER 1:"Identification of novel subgroups of high-risk pediatric precursor B acute lymphoblastic leukemia (B-ALL) by unsupervised microarray analysis: clinical correlates and therapeutic implications. A Children's Oncology Group (COG) study." ABSTRACT We examined gene expression profiles of pre-treatment specimens from 207 patients from the COG P9906 study to identify signatures of children with high risk B-precursor acute lymphoblastic leukemia (ALL) and to determine whether the resulting clusters are associated with either specific clinical features or treatment response characteristics. Four unsupervised clustering methods were utilized to classify patients into similar groups. The different clustering algorithms showed significant overlap in cluster membership. Two clusters contained all cases with either t(1;19)(q23;p13) translocations or MLL rearrangements. The other six clusters were novel and had no recurring chromosomal abnormalities or distinctive clinical features. Members of two of these novel clusters had significant survival differences when compared to the overall 4-year relapse-free survival (RFS) of 61%. These included clusters of patients with either significantly better (94.7%) or worse (21.0%) RFS at 4 years. Children of Hispanic/Latino ethnicity were disproportionately present in the poor outcome cluster. The poor outcome cluster represents a novel biologically distinctive subset of B-precursor ALL that may occur at least as frequently as BCR/ABL. Further molecular characterization of this cluster may lead to the discovery of genomic abnormalities that can be targeted to improve the currently dismal outcome for children with this gene signature. The Sample data have also been used in another study: PAPER 2: "Gene expression classifiers for minimal residual disease and relapse free survival improve outcome prediction and risk classification in children with high risk acute lymphoblastic leukemia. A Children's Oncology Group study". ABSTRACT Background. Nearly 25% of children with B-precursor ALL present with "high-risk" disease (HR-ALL) that is resistant to current therapies. Gene expression profiling may yield molecular classifiers for outcome prediction that can be used to improve risk classification and therapeutic targeting. Methods. Expression profiles were obtained in pre-treatment leukemic samples from 207 uniformly treated children with HR-ALL. Relapse free survival (RFS) was 61% at 4 years and flow cytometric measures of minimal residual disease (MRD) at the end of induction (day 29) were predictive of outcome (P<0.001). Molecular classifiers predictive of RFS and MRD were developed using extensive cross-validation procedures. Results. A 38 gene molecular risk classifier predictive of RFS (MRC-RFS) distinguished two groups in HR-ALL with different relapse risks: low (4 yr RFS: 81%, n=109) vs. high (4 yr RFS: 50%, n=98) (P<0.0001). In multivariate analysis, the best predictor combined MRC-RFS and day 29 flow MRD data, classifying children into low (87% RFS), intermediate (62% RFS), or high risk (29% RFS) groups (P<0.0001). A 21 gene molecular classifier predictive of MRD could effectively substitute for day 29 flow MRD, yielding a combined classifier that similarly distinguished three risk groups at pre-treatment (low: 82% RFS; intermediate: 63% RFS; and high risk: 45% RFS) (P<0.0001). This combined molecular classifier was further validated on an independent cohort of 84 children with HR-ALL (P = 0.006). Conclusions. Molecular classifiers predictive of RFS and MRD can be used to distinguish distinct prognostic groups within HR-ALL, significantly improving risk classification schemes and the ability to prospectively identify children at diagnosis who will respond to or fail current treatment regimens. NOTE: Due to Children's Oncology Group (COG) restrictions, outcome and MRD data cannot be provided as part of the covariate data for this dataset at the present time. If you would like to arrange individual access to this data, please contact COG or the PI of this study, Dr. Cheryl Willman, at the University of New Mexico Cancer Center (cwillman@unm.edu) to arrange a collaboration.
2009-06-25 | GSE11877 | GEO
Project description:PAPER 1:"Identification of novel subgroups of high-risk pediatric precursor B acute lymphoblastic leukemia (B-ALL) by unsupervised microarray analysis: clinical correlates and therapeutic implications. A Children's Oncology Group (COG) study." ABSTRACT We examined gene expression profiles of pre-treatment specimens from 207 patients from the COG P9906 study to identify signatures of children with high risk B-precursor acute lymphoblastic leukemia (ALL) and to determine whether the resulting clusters are associated with either specific clinical features or treatment response characteristics. Four unsupervised clustering methods were utilized to classify patients into similar groups. The different clustering algorithms showed significant overlap in cluster membership. Two clusters contained all cases with either t(1;19)(q23;p13) translocations or MLL rearrangements. The other six clusters were novel and had no recurring chromosomal abnormalities or distinctive clinical features. Members of two of these novel clusters had significant survival differences when compared to the overall 4-year relapse-free survival (RFS) of 61%. These included clusters of patients with either significantly better (94.7%) or worse (21.0%) RFS at 4 years. Children of Hispanic/Latino ethnicity were disproportionately present in the poor outcome cluster. The poor outcome cluster represents a novel biologically distinctive subset of B-precursor ALL that may occur at least as frequently as BCR/ABL. Further molecular characterization of this cluster may lead to the discovery of genomic abnormalities that can be targeted to improve the currently dismal outcome for children with this gene signature. The Sample data have also been used in another study: PAPER 2: "Gene expression classifiers for minimal residual disease and relapse free survival improve outcome prediction and risk classification in children with high risk acute lymphoblastic leukemia. A Children's Oncology Group study". ABSTRACT Background. Nearly 25% of children with B-precursor ALL present with "high-risk" disease (HR-ALL) that is resistant to current therapies. Gene expression profiling may yield molecular classifiers for outcome prediction that can be used to improve risk classification and therapeutic targeting. Methods. Expression profiles were obtained in pre-treatment leukemic samples from 207 uniformly treated children with HR-ALL. Relapse free survival (RFS) was 61% at 4 years and flow cytometric measures of minimal residual disease (MRD) at the end of induction (day 29) were predictive of outcome (P<0.001). Molecular classifiers predictive of RFS and MRD were developed using extensive cross-validation procedures. Results. A 38 gene molecular risk classifier predictive of RFS (MRC-RFS) distinguished two groups in HR-ALL with different relapse risks: low (4 yr RFS: 81%, n=109) vs. high (4 yr RFS: 50%, n=98) (P<0.0001). In multivariate analysis, the best predictor combined MRC-RFS and day 29 flow MRD data, classifying children into low (87% RFS), intermediate (62% RFS), or high risk (29% RFS) groups (P<0.0001). A 21 gene molecular classifier predictive of MRD could effectively substitute for day 29 flow MRD, yielding a combined classifier that similarly distinguished three risk groups at pre-treatment (low: 82% RFS; intermediate: 63% RFS; and high risk: 45% RFS) (P<0.0001). This combined molecular classifier was further validated on an independent cohort of 84 children with HR-ALL (P = 0.006). Conclusions. Molecular classifiers predictive of RFS and MRD can be used to distinguish distinct prognostic groups within HR-ALL, significantly improving risk classification schemes and the ability to prospectively identify children at diagnosis who will respond to or fail current treatment regimens. NOTE: Due to Children's Oncology Group (COG) restrictions, outcome and MRD data cannot be provided as part of the covariate data for this dataset at the present time. If you would like to arrange individual access to this data, please contact COG or the PI of this study, Dr. Cheryl Willman, at the University of New Mexico Cancer Center (cwillman@unm.edu) to arrange a collaboration. Unsupervised clustering and supervised risk classification analyses of 207 diagnostic samples and associated clinical covariate data. See the Summary for greater details. The data were analyzed using Microarray Suite version 5.0 (MAS 5.0) in the Affymetrix Gene Chip Operating Software Version 1.4. Probe masking was used (see 9906_TT207_Affymetrix_probe_mask.msk, linked below as a supplementary file). Otherwise all Affymetrix default parameter settings were used. Global scaling as the normalization method, with the default target intensity of 500, was used.
2009-06-25 | E-GEOD-11877 | biostudies-arrayexpress