Investigation of relapse prediction in infants with MLL-rearranged Acute Lymphoblastic Leukemia
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PROVIDER: EGAS00001003986 | EGA |
REPOSITORIES: EGA
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Project description:Acute myeloid leukemia (AML) is characterized by serious aggressivity of high relapse risk and various molecular aberrations. Rearrangements involving NUP98 with multiple fusing partner genes in myeloid malignancies indicate dismal survival outcomes. Mechanisms contributing to subsequent aggressive progression and severe relapse risk of NUP98-rearranged AML remain undefined. Here we identified a novel oncogenic fusion RUNX1/ZNF423 in a relapse and refractory AML patient with NUP98/NSD1. And mice xenografted from the patient bearing both RUNX1/ZNF423 and NUP98/NSD1 display more severe engraftment levels than NUP98/NSD1 only. Mechanically, RUNX1/ZNF423 accompanied with NUP98/NSD1 recapitulated transcriptional signatures in hematopoietic differentiation blockage and altered amino acid metabolism pathway. Moreover, single-cell sequencing confirmed the coexistence of RUNX1/ZNF423 with NUP98/NSD1 in the same leukemic blast. Meanwhile, we also found that the coexistence of gene fusions in NUP98-rearranged AML was a significant phenomenon, which probably contributes to their worse clinical outcome. Finally, tailored intervention treatment based on ex vivo drug sensitivity testing is provided to this relapse and refractory AML patient and achieved favorable clinical response. Taken together, we not only identified a novel gene fusion RUNX1/ZNF423 with transforming potential detected in a NUP98-rearranged AML, but also achieved a deeper understanding into mechanisms contributing to disease relapse in AML.
2024-12-01 | GSE222098 | GEO
Project description:In neuroblastoma (NB), the presence of segmental chromosome alterations (SCA) is associated with a higher risk of relapse, even when occurring together with numerical chromosome alterations (NCA). Furthermore, recent evidence shows that SCAs play a role in tumor progression. In order to analyze the role of SCAs in infants with NB, we have performed an extensive retrospective array-CGH analysis of tumours from infants enrolled in the European INES 99.1, 99.2 and 99.3 trials. Tumour samples from 221/300 enrolled patients could be analyzed. SCAs were observed in 11%, 20% and 59% of infants enrolled in trial 99.1 (localised unresectable NB), 99.2 (INSS stage 4s) and 99.3 (INSS stage 4), respectively (p<0.001), and were associated with the presence of bone metastasis (p<0.003). Progression-free survival was poorer in patients whose tumours harbored at least one SCA, in the whole population as well as in trials 99.1 and 99.2. In multivariate analysis, taking into account single genetic alterations, the protocol arm and genomic profile, the SCA genomic profile was the strongest predictor of poor outcome. Although overall survival was excellent, patients with stage 4s disease and a SCA genomic profile had a higher risk of relapse also in the absence of clinical symptoms at diagnosis and required a higher treatment burden for salvage. In conclusion, in infants with NB, a SCA genomic profile is useful to identify patients who will require upfront treatment even in the absence of other clinical indication for therapy, whereas an NCA genomic profile can identify a patient subpopulation in whom treatment reduction can be considered safe. Each of the 218 tumoral genomic DNAs was hybridized against non-tumoral DNA reference on BAC/PAC array or commercial supports in order to determine an overall genomic profile. The reference DNA was obtained from the blood of a single normal individual.
2011-12-07 | E-GEOD-26494 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is characterized by serious aggressivity of high relapse risk and various molecular aberrations. Rearrangements involving NUP98 with multiple fusing partner genes in myeloid malignancies indicate dismal survival outcomes. Mechanisms contributing to subsequent aggressive progression and severe relapse risk of NUP98-rearranged AML remain undefined. Here we identified a novel oncogenic fusion RUNX1/ZNF423 in a relapse and refractory AML patient with NUP98/NSD1. And mice xenografted from the patient bearing both RUNX1/ZNF423 and NUP98/NSD1 display more severe engraftment levels than NUP98/NSD1 only. Mechanically, RUNX1/ZNF423 accompanied with NUP98/NSD1 recapitulated transcriptional signatures in hematopoietic differentiation blockage and altered amino acid metabolism pathway. Moreover, single-cell sequencing confirmed the coexistence of RUNX1/ZNF423 with NUP98/NSD1 in the same leukemic blast. Meanwhile, we also found that the coexistence of gene fusions in NUP98-rearranged AML was a significant phenomenon, which probably contributes to their worse clinical outcome. Finally, tailored intervention treatment based on ex vivo drug sensitivity testing is provided to this relapse and refractory AML patient and achieved favorable clinical response. Taken together, we not only identified a novel gene fusion RUNX1/ZNF423 with transforming potential detected in a NUP98-rearranged AML, but also achieved a deeper understanding into mechanisms contributing to disease relapse in AML.
2024-12-01 | GSE221767 | GEO
Project description:In neuroblastoma (NB), the presence of segmental chromosome alterations (SCA) is associated with a higher risk of relapse, even when occurring together with numerical chromosome alterations (NCA). Furthermore, recent evidence shows that SCAs play a role in tumor progression. In order to analyze the role of SCAs in infants with NB, we have performed an extensive retrospective array-CGH analysis of tumours from infants enrolled in the European INES 99.1, 99.2 and 99.3 trials. Tumour samples from 221/300 enrolled patients could be analyzed. SCAs were observed in 11%, 20% and 59% of infants enrolled in trial 99.1 (localised unresectable NB), 99.2 (INSS stage 4s) and 99.3 (INSS stage 4), respectively (p<0.001), and were associated with the presence of bone metastasis (p<0.003). Progression-free survival was poorer in patients whose tumours harbored at least one SCA, in the whole population as well as in trials 99.1 and 99.2. In multivariate analysis, taking into account single genetic alterations, the protocol arm and genomic profile, the SCA genomic profile was the strongest predictor of poor outcome. Although overall survival was excellent, patients with stage 4s disease and a SCA genomic profile had a higher risk of relapse also in the absence of clinical symptoms at diagnosis and required a higher treatment burden for salvage. In conclusion, in infants with NB, a SCA genomic profile is useful to identify patients who will require upfront treatment even in the absence of other clinical indication for therapy, whereas an NCA genomic profile can identify a patient subpopulation in whom treatment reduction can be considered safe.
2011-12-07 | GSE26494 | GEO
Project description:We report the results of a study in which we sought to identify the patients at risk of relapse by using a transcriptomic approach and to clarify the molecular abnormalities that define tumors at risk of relapse. We used pangenomic oligoarrays (Agilent) and hybridized primary tumor with relapse versus primary tumor without relapse
2010-11-04 | E-MTAB-154 | biostudies-arrayexpress
Project description:Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a prospective case–control analysis to identify the drivers of immune activation in infants and found cytomegalovirus (CMV) stimulated IFN-γ-expressing cells to be associated with CD8+ T cell activation (Spearman’s rho r = 0.241, p <0.0001). Among 49 infants who developed incident TB disease and 129 matched controls who remained healthy we found that CMV and Epstein–Barr virus (EBV) specific IFN-γ responses were associated with increased risk of developing TB (Fisher’s Exact Test, p=0.049, OR 2.14, 95% CI 1.03-4.47), and associated with a shorter time to TB diagnosis (Log Rank Mantel-Cox p=0.012). T cell activation and CMV are associated with lower mycobacterial antigen-specific immune responses following immunization with Bacille Calmette-Guerin (BCG) and MVA85A, suggesting that increased susceptibility to TB in infants with virus infection may, in part, be due to poor responsiveness to vaccination. Understanding of the causes and impact of T cell activation could transform strategies used to protect against TB disease.
2018-12-05 | GSE98550 | GEO
Project description:The prevalence of immune-mediated diseases such as allergies and autoimmune diseases is on the rise in the developed world. Microbial exposure is known to modulate the risk for these diseases. In order to explore differences in the gene expression patterns induced in utero in infants born in contrasting standards of living and hygiene, we collected umbilical cord blood RNA samples from full-term newborn infants born with normal vaginal delivery in Finland (modern society), Estonia (rapidly developing society) and the Republic of Karelia, Russia (poor economical conditions). Transcriptomic profiles were analyzed using whole genome microarrays including gender, gestational age, birth month and HLA allele genotype as confounding variables in the analysis. The data revealed that the whole blood transcriptome of Finnish and Estonian neonates differ from their Karelian counterparts. Samples from Karelian infants had an increase in transcripts associated with LPS induction and bacterial sepsis observed in 1-year-old infants in earlier studies. The results suggest exposure to toll like receptor (TLR) ligands and a more matured immune response in infants born in Petrozavodsk compared to the Finnish and Estonian infants. These results further support the concept of a conspicuous plasticity in the developing immune system: the environmental factors that play a role in the susceptibility/protection towards immune-mediated diseases begin to shape the neonatal immunity already in utero and direct the maturation of both the adaptive and the innate immune responses in accordance with the surrounding microbial milieu. Umbilical cord blood was drawn into Tempus Blood RNA tubes (Applied Biosystems) from children born between January and May 2010 at the maternity unit of Jorvi hospital (Espoo, Finland; n=48), maternity units of Tartu and PM-CM-5lva (Estonia; n=25), or two maternity departments in Petrozavodsk (capital of the Republic of Karelia, Russian Federation; n=40) according to the manufacturerM-BM-4s protocol and then stored in M-bM-^HM-^R70 M-BM-0C until analyzed. All newborn infants were full-term (>36 gestational weeks) and born vaginally. 113 cord blood RNA samples were analyzed with Affymetrix U219 gene array. Gender, pregnancy week, month of birth and HLA risk class were included as confounding factors in the analysis model.
2014-09-25 | E-GEOD-53471 | biostudies-arrayexpress
Project description:Objective: A subset of Crohns disease (CD) patients experiences long-term remission after infliximab withdrawal. Biomarkers are needed to identify those patients.Design: New biomarkers of relapse were searched in the baseline serum of CD patients stopping infliximab when they were under combined therapy (antimetabolite and infliximab) and stable clinical remission (STORI cohort, n=102). From shotgun proteomics experiment (discovery step), biomarker candidates were identified and further targeted by selected reaction monitoring (verification step). The dataset was stratified to search for markers of short- (<6 months) or long-term relapse (>6 months). The risk of relapse and the predicting capacity associated with biomarker candidates were evaluated using univariate Cox model and log-rank statistic, respectively. To test their complementary predicting capacity, biomarker candidates were systematically combined in pairs. Results: Distinct biomarker candidates were associated with the risk (hazard ratio: HR) of short- (15 proteins, 2.9<HR<16.1, p<0.05) and long-term (17 proteins, 2<HR<4.4, p<0.05) relapse, they reflect different pathophysiological processes. In stratified and non-stratified datasets, novel marker combinations exhibited a high predicting capacity as shown by their higher Z-scores (FDR<0.001) than CRP and faecal calprotectin (current references in predicting relapse). Conclusion: We identified for the first time circulating biomarker candidates associated with the risk of long-term relapse in CD patients stopping infliximab. We also highlight a sequence of pathophysiological processes leading to relapse, this could help to better understand the disease progression. Our findings may pave the way for a better non-invasive evaluation of the risk of relapse when contemplating anti-TNFα withdrawal in CD patients.
2020-10-19 | PXD019008 | Pride
Project description:Relapse is the most common cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL) and is often difficult to predict. To explore the prognostic impact of recurrent DNA copy number abnormalities on relapse, we performed high-resolution genomic profiling of 34 paired diagnosis-relapse ALL samples. Recurrent lesions detected at diagnosis, including PAX5, CDKN2A, and EBF1, were frequently absent at relapse, indicating that they represent secondary events that may be absent in the relapse-prone therapy-resistant progenitor cell. In contrast, deletions and nonsense mutations in IKZF1 (IKAROS), were highly enriched and consistently preserved at the time of relapse. A targeted copy number screen in an unselected cohort of 131 precursor B-ALL cases, enrolled in the dexamethasone-based Dutch Childhood Oncology Group treatment protocol ALL9, revealed that IKZF1 deletions are significantly associated with poor relapse-free and overall survival rates. Separate analysis of ALL9-treatment subgroups revealed that non-high-risk patients with IKZF1 deletions exhibited a ~12-fold higher relative relapse rate than those without IKZF1 deletions. Consequently, IKZF1 deletion status allowed the prospective identification of 53% of the relapse-prone non-high-risk-classified patients within this subgroup and, therefore, serves as one of the strongest predictors of relapse at the time of diagnosis with high potential for future risk stratification. Affymetrix NspI 250k array data of 34 paired diagnosis and relapse samples of pediatric ALL. From 13 patients a complete remission sample was available. Four cases had 2 relapses.
2010-03-01 | GSE20353 | GEO
Project description:We procured peripheral whole blood from ten healthy preterm infants and ten preterm infants with bronchopulmonary dysplasia
2024-10-27 | E-MTAB-14506 | biostudies-arrayexpress