Label-free quantitative proteomics reveals differentially expressed proteins in high risk childhood acute lymphoblastic leukemia

2017 ◽  
Vol 150 ◽  
pp. 1-8 ◽  
Author(s):  
Gang Xu ◽  
Zhijie Li ◽  
Lili Wang ◽  
Fang Chen ◽  
Zuofei Chi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Quantitative Proteomics ◽  
Lymphoblastic Leukemia ◽  
Differentially Expressed ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Differentially Expressed Proteins ◽  
Label Free

Focal 22q11.22 Loss Combined with IKZF1 Alterations Predict Very Poor Outcome in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 741-741
Author(s):  
D. Spencer Mangum ◽  
Soheil Shams ◽  
Jonathan M. Downie ◽  
Uta von Schwedler ◽  
Vladimir Rodic ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Differentially Expressed Genes ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Differentially Expressed ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Childhood All ◽  
Poor Outcome

Abstract Abstract 741 Identifying prognostic biomarkers in childhood acute lymphoblastic leukemia (ALL) is imperative for risk-stratification and intensifying therapy for children at high risk of remission induction failure or relapse. IKZF1 deletions/mutations were recently shown to correlate with poor outcome in ALL, highlighting genetic alterations as prognostic markers (NEJM 360:470, 2009). We recently described focal deletions in VPREB1 located within the lambda variable chain region which are not part of normal light chain rearrangement in precursor B-cell ALL in a local Utah cohort and the TARGET cohort of high-risk ALL patients treated on the Children's Oncology Group P9906 trial. Upon further inspection, we identified a second focal deletion in chromosome 22q11.22, nearly 80 kilobases (Kb) upstream from VPREB1 in the same lambda region. We characterized and correlated this deletion with outcome in childhood ALL using the Utah Cohort (N=60), TARGET P9906 cohort (N=221), and St. Jude Children's Research Hospital cohort (SJCRH, N=298). Microarray data was analyzed (Utah = Molecular Inversion Probe 330K [Affymetrix]; TARGET = SNP 500K & U133A [Affymetrix]; SJCRH = SNP 500K/6.0 & U133A [Affymetrix]) by Nexus Copy Number and Nexus Expression (BioDiscovery, Inc.). Each cohort contains the focal 22q11.22 loss (Hemizygous: Utah = 21%, TARGET = 16%, SJCRH = 18%; and Homozygous: Utah = 7%, TARGET = 16%, SJCRH = 10%). It spans 142 Kb, with the most common recurring region just under 10 Kb in length. The deleted segment encodes no known genes. In the SJCRH cohort, 22q11.22 loss differs by subtype: Down's syndrome 93%, BCR-ABL1 47%, ETV6-RUNX1 46%, Pseudodiploid 38%, Hyperdiploid 30%, Other 33%, MLL 12%, TCF3-PBX1 12%, T-ALL 7%, Hypodiploid 0%. In the TARGET cohort, 22q11.22 loss confers a trend for worse event-free survival (EFS; P=0.17) and overall survival (OS; P=0.06). Compared to normal 22q11.22/IKZF1 (77% EFS) or IKZF1 alternations alone (45% EFS), combined 22q11.22 loss plusIKZF1 alterations drastically reduces EFS to 15% (P<0.0001). This pattern was validated in the larger SJCRH cohort with worse outcome for isolated 22q11.22 loss (EFS; P=0.03, and OS; P=0.02). Once again, compared to normal 22q11.22/IKZF1 (EFS 76%, OS 87%) or IKZF1 alterations alone (EFS 61%, OS 80%), 22q11.22 loss plusIKZF1 alterations reduces EFS to 23% (P<0.0001) and OS to 48% (P<0.0001). In the SJCRH cohort, multiple Cox regression including subtype, age, and WBC reveals that combined 22q11.22/IKZF1 alterations independently predict worse EFS (HR 5.568 [95% CI 2.6–11.7], P<0.0001) and OS (HR 4.989 [95% CI 1.8–13.9], P=0.0021). To understand the basis of this combined worse outcome, we analyzed paired gene expression data for the TARGET (N=198) and SJCRH (N=146) cohorts. We looked for differentially expressed genes in common between both cohorts and included only samples with 22q11.22 homozygous loss to capture the most pronounced effects of the deleted region. We compared: 1) 22q11.22 normal vs. 22q11.22 loss in IKZF1 normal samples, 2) IKZF1 normal vs. IKZF1 alterations in 22q11.22 normal samples, and 3) normal samples vs. combined 22q11.22/IKZF1 altered samples. CCND2 was upregulated 2.1-fold in isolated 22q11.22 loss samples, 1.4-fold in isolated IKZF1 altered samples, and increased to 2.6-fold in combined 22q11.22 loss plusIKZF1 altered samples. Of 23 genes affected by combined 22q11.22/IKZF1 alterations, 9 were associated with resistance to at least one of 4 commonly use antileukemic agents (prednisolone, vincristine, asparaginase, and daunorubicin) in primary ALL based on a previously published dataset (NEJM 351:533,2004; N=177). For example, CCND2 over-expression in diagnostic ALL blasts significantly associated with higher LC50 (resistance) for daunorubicin (P=0.002) and prednisolone (P=0.005). Gene Ontology enrichment for differentially expressed genes in combined 22q11.22/IKZF1 altered samples was significant for anti-apoptosis (P=0.001) and cell growth (P=0.005) biological processes. In summary, we discovered and validated that 22q11.22 loss independently contributes to worse outcome in pediatric ALL in the presence of IKZF1 genetic alterations. These combined alterations may be useful to identify patients with very poor outcomes in childhood ALL. Further work to understand the mechanism of the synergistic effect of combined 22q11.22 loss plusIKZF1 alterations is underway. Disclosures: Shams: BioDiscovery, Inc.: Employment.

scholarly journals High-Risk Childhood Acute Lymphoblastic Leukemia

2009 ◽  
Vol 9 ◽  
pp. S222-S230 ◽  
Author(s):  
Deepa Bhojwani ◽  
Scott C. Howard ◽  
Ching-Hon Pui
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia

scholarly journals Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 409-415 ◽  
Author(s):  
SB Murphy ◽  
SC Raimondi ◽  
GK Rivera ◽  
M Crone ◽  
RK Dodge ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Clinical Features ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
Term Survival ◽  
Childhood All ◽  
Chromosome 9P

To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

scholarly journals Response Adapted Therapy in ETV6/RUNX1-Positive Childhood Acute Lymphoblastic Leukemia Treated per Modified St Jude Total XV Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Mayada Abu Shanap ◽  
Iyad Sultan ◽  
Amal Abu-Ghosh ◽  
Hasan Hashem ◽  
Abdelghani Tbakhi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Induction Therapy ◽  
Leukocyte Count ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Low Risk ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Standard Risk

Introduction: ETV6-RUNX1 is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a precursor-B phenotype. The presence of ETV6-RUNX1 has been associated with a relatively low rate of relapse in multiple studies. Relapses tend to occur late and have a better salvage rate than other ALL subtypes. Moreover, conflicting data in literature regarding the prognostic significance of ETV6-RUNX1 after accounting for age, initial count and treatment intensity. We sought to study the clinical features, therapy response in newly diagnosed ETV6-RUNX1-positive treated at King Hussein Cancer Center. Methods: Patients were treated per modified St Jude Total (XV) study, risk stratification was further refined by including minimal residual disease (MRD)measurements on day 15 and day 46 of remission induction therapy. Patients with the ETV6- RUNX1 fusion or hyperdiploidy without CNS or testicular disease and a satisfactory early MRD decline (&lt;1% on day 15 and &lt;0.01% on day 46) were classified as being low-risk for relapse and were treated on lower -risk arm regardless of age and leukocyte count. Results: Seventy patients (n=70) with ETV6-RUNX1-positive treated at our institution between May 2006 to October 2017. The median age at diagnosis, 5.8 years (range, 1.5-10.8). ETV6-RUNX1 was associated with favorable age between 1- and 6-years in 55 patients (79%), male gender in 41 patients (59%), initial leukocyte count &lt;10 in 39 patients (56%), CNS status 1 in 100% of patients. The majority, n= 58 (83%) of patients had NCI standard risk (SR) and n=12 (17%) had NCI high risk (HR). Sixty-six patients (94%) had MRD &lt;1% at day 15 and all patients achieved remission with MRD&lt;0.01% at day 46 of remission induction. All patients were treated as LR ALL per modified St Jude total XV protocol. At median follow up of (36 months; range, 26 to 154), in the subgroups of ETV6-RUNX1-positive patients classified as NCI standard risk (SR)and NCI high risk (HR) the 5-year EFS estimates were 94.1% ± 3.2 and 82%±1(P=.13), 5-year OS estimates were 100% and 92% ± 8 (p=0.31) respectively. Conclusion: MRD treatment schema in ETV6/RUNX1 -positive patients have excellent outcomes if they achieved favorable response at day 15 and end of remission induction regardless of the age and Initial leukocyte count. Treatment reduction is feasible and declared safe for children with NCI-HR who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD post remission induction therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparative proteome analysis of the spinal dural arteriovenous fistula arterial draining vein with label-free quantitative proteomics

2020 ◽  
Author(s):  
Peixi Liu ◽  
Yuan Shi ◽  
Sichen Li ◽  
Yingjun Liu ◽  
Yingjie Zhou ◽  
...  
Keyword(s):  
Quantitative Proteomics ◽  
Dural Arteriovenous Fistula ◽  
Kegg Pathway ◽  
Differentially Expressed ◽  
Differentially Expressed Proteins ◽  
Label Free ◽  
Spinal Dural Arteriovenous Fistula ◽  
Differentially Expressed Protein ◽  
Kegg Pathway Analysis ◽  
Go Terms

Abstract Background: Spinal dural arteriovenous fistula (SDAVF) is the most common spinal vascular shunt lesion. Although pathological changes in the SDAVF draining vein (SDAVF-DV) have been elucidated, protein changes remain enigmatic. We investigated protein changes in the SDAVF-DV.Methods: Three SDAVF-DV samples were collected, and superficial temporal artery (STA) and superficial temporal vein (STV) samples were used as controls. After quantification and enzymolysis of the proteins, label-free quantitative proteomics was performed, and the peptide mixture was fractionated and analysed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify the differentially expressed proteins. Bioinformatics analysis of the differentially expressed proteins was also performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analyses.Results: Compared with the STA, the SDAVF-DV had 195 upregulated proteins and 303 downregulated proteins. GO analysis showed that the most differential GO terms in each category were the adenylate cyclase-modulating G protein-coupled receptor signalling pathway, U6 snRNP and SH3 domain binding. KEGG pathway analysis showed that the most differentially expressed protein pathway was focal adhesion. Compared with the STV, the SDAVF-DV had 158 upregulated proteins and 362 downregulated proteins. GO analysis showed that the most differential GO terms in each category were lamellipodium assembly, U6 snRNP, and SH3 domain binding. KEGG pathway analysis showed that the most differentially expressed protein pathway was dilated cardiomyopathy. The PPI analysis revealed PPIs among the top 300 proteins.Conclusions: We demonstrated that the SDAVF-DV showed specific protein expression changes under long-period venous hypertension. The results of the present study will provide insights into the pathogenesis of SDAVF formation at the protein level. The proteomic results provide a scientific foundation for further study to explore the pathophysiological mechanism of SDAVF.

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