Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia.

ABSTRACT: Somatic CBL mutations have been reported in a variety of myeloid neoplasms but are rare in acute lymphoblastic leukemia (ALL). We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML. Two NOTCH1 mutations and homozygous deletions in LEF1 and CDKN2A were identified in T-ALL cells. The activation of the RAS pathway was enhanced, and activation of the NOTCH1 pathway was inhibited in NIH 3T3 cells that expressed p.C381R. This study appears to be the first to identify a CBL mutation in T-ALL.

SUBMITTER: Saito Y

PROVIDER: S-EPMC3693942 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia.

Saito Yuka Y Aoki Yoko Y Muramatsu Hideki H Makishima Hideki H Maciejewski Jaroslaw P JP Imaizumi Masue M Rikiishi Takeshi T Sasahara Yoji Y Kure Shigeo S Niihori Tetsuya T Tsuchiya Shigeru S Kojima Seiji S Matsubara Yoichi Y

Leukemia research 20120514 8

Somatic CBL mutations have been reported in a variety of myeloid neoplasms but are rare in acute lymphoblastic leukemia (ALL). We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML. Two NOTCH1 mutations and homozygous deletions in LEF1 and CDKN2A were identified in T-ALL cells. The activation of the ...[more]

PMID: 22591685

Similar Datasets

Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study.

Project description:The survival of pediatric patients with multiply relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia has historically been very poor; however, data are limited in the current era. We conducted a retrospective study to determine the outcome of multiply R/R childhood B-ALL treated at 24 TACL institutions between 2005 and 2013. Patient information, treatment, and response were collected. Prognostic factors influencing the complete remission (CR) rate and event-free survival (EFS) were analyzed. The analytic set included 578 salvage treatment attempts among 325 patients. CR rates (mean?±?SE) were 51?±?4% for patients with bone marrow R/R B-ALL who underwent a second salvage attempt, 37?±?6% for a third attempt, and 31?±?6% for the fourth through eighth attempts combined. For patients achieving a CR after their second, third, and fourth through eighth attempts, the 2 year EFS was 41?±?6%, 13?±?7%, and 27?±?13% respectively. Our results showed slight improvement when compared to previous studies. This is the largest and most recent study to date that evaluates the outcome of this patient population. Our data will provide detailed reference for the evaluation of new agents being developed for childhood B-ALL.

| S-EPMC6224404 | biostudies-literature

Proteogenomics of High hyperdiploid childhood acute lymphoblastic leukemia

Project description:Proteogenomic analysis and genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of High hyperdiploid childhood acute lymphoblastic leukemia.

2019-02-25 | PXD010175 | Pride

High-risk childhood acute lymphoblastic leukemia.

Project description:Although most children with acute lymphoblastic leukemia (ALL) are cured, certain subsets have a high risk of relapse. Relapse risk can be predicted by early response to therapy, clinical and pharmacogenetic features of the host, and genetic characteristics of leukemic cells. Though early treatment response can be assessed by the peripheral blast cell count after 1 week of single-agent glucocorticoid treatment or percent of bone marrow blasts by morphology after 1 or 2 weeks of multiagent induction treatment, determination of minimal residual disease by polymerase chain reaction (PCR) or flow cytometry after 2 to 6 weeks of induction is the most precise and useful measure. Augmented therapy has improved outcome for the poor responders to initial treatment. Infants with mixed-lineage leukemia (MLL)-rearranged ALL comprise a very poor-risk group wherein further intensification of chemotherapy causes significant toxicity. Hybrid protocols incorporating drugs effective for acute myeloid leukemia could improve survival, a strategy being tested in international trials. Studies on the biology of MLL-induced leukemogenesis have prompted the development of novel targeted agents, currently under evaluation in clinical trials. Short-term outcomes of patients with Philadelphia chromosome (Ph)-positive ALL have improved significantly by adding tyrosine kinase inhibitors to standard chemotherapy regimens. New agents and methods to overcome resistance are under investigation, and allogeneic stem cell transplantation is recommended for certain subsets of patients, for example those with Ph+ and T-cell ALL with poor early response. Genome-wide interrogation of leukemic cell genetic abnormalities and germline genetic variations promise to identify new molecular targets for therapy.

| S-EPMC2814411 | biostudies-literature

Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia.

Project description:WNT signaling has been implicated in the regulation of hematopoietic stem cells and plays an important role during T-cell development in thymus. Here we investigated WNT pathway activation in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. To evaluate the potential role of WNT signaling in T-cell leukomogenesis, we performed expression analysis of key components of WNT pathway. More than 85% of the childhood T-ALL patients showed upregulated β-catenin expression at the protein level compared with normal human thymocytes. The impact of this upregulation was reflected in high expression of known target genes (AXIN2, c-MYC, TCF1 and LEF). Especially AXIN2, the universal target gene of WNT pathway, was upregulated at both mRNA and protein levels in ∼40% of the patients. When β-CATENIN gene was silenced by small interfering RNA, the cancer cells showed higher rates of apoptosis. These results demonstrate that abnormal WNT signaling activation occurs in a significant fraction of human T-ALL cases independent of known T-ALL risk factors. We conclude that deregulated WNT signaling is a novel oncogenic event in childhood T-ALL.

| S-EPMC3972698 | biostudies-literature

Current Use of Asparaginase in Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma.

Project description:Pediatric Acute Lymphoblastic Leukemia (ALL) cure rates have improved exponentially over the past five decades with now over 90% of children achieving long-term survival. A direct contributor to this remarkable feat is the development and expanded understanding of combination chemotherapy. Asparaginase is the most recent addition to the ALL chemotherapy backbone and has now become a hallmark of therapy. It is generally accepted that the therapeutic effects of asparaginase is due to depletion of the essential amino acid asparagine, thus occupying a unique space within the therapeutic landscape of ALL. Pharmacokinetic and pharmacodynamic profiling have allowed a detailed and accessible insight into the biochemical effects of asparaginase resulting in regular clinical use of therapeutic drug monitoring (TDM). Asparaginase's derivation from bacteria, and in some cases conjugation with a polyethylene glycol (PEG) moiety, have contributed to a unique toxicity profile with hypersensitivity reactions being the most salient. Hypersensitivity, along with several other toxicities, has limited the use of asparaginase in some populations of ALL patients. Both TDM and toxicities have contributed to the variety of approaches to the incorporation of asparaginase into the treatment of ALL. Regardless of the approach to asparagine depletion, it has continually demonstrated to be among the most important components of ALL therapy. Despite regular use over the past 50 years, and its incorporation into the standard of care treatment for ALL, there remains much yet to be discovered and ample room for improvement within the utilization of asparaginase therapy.

| S-EPMC9279693 | biostudies-literature

Epigenetic Priming in Childhood Acute Lymphoblastic Leukemia.

Project description:Leukemogenesis is considered to be a process by which a normal cell acquires new but aberrant identity in order to disseminate a malignant clonal population. Under this setting, the phenotype of the leukemic cells is identical to the leukemia-initiating cell in which the genetic insult is taking place. Thus, with some exceptions, B-cell and T-cell childhood leukemias are supposed to arise from B- or T-committed cells. In contrast, several recent studies have revealed that genetic alterations may act in a "hit-and-run" way in the cell-of-origin by imposing the tumor cell identity giving rise to either B-cell or T-cell leukemias. This novel mechanism of cell transformation is mediated by an epigenetic priming mechanism that is established by the initial genetic lesion. This initial hit might be unnecessary for the subsequent tumor evolution and conservation, being the epigenetic priming the engine for the tumor evolution.

| S-EPMC6652134 | biostudies-literature

Genomic characterization of childhood acute lymphoblastic leukemia.

Project description:Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading case of childhood cancer death. The last decade has witnessed a transformation in our understanding of the genetic basis of ALL due to detailed integrative genomic profiling of large cohorts of childhood ALL. Initially using microarray based approaches, and more recently with next-generation sequencing, these studies have enabled more precise subclassification of ALL, and have shown that each ALL entity is characterized by constellations of structural and sequence mutations that typically perturb key cellular pathways including lymphoid development, cell cycle regulation, tumor suppression, Ras- and tyrosine kinase-driven signaling, and epigenetic regulation. Importantly, several of the newly identified genetic alterations have entered the clinic to improve diagnosis and risk stratification, and are being pursued as new targets for therapeutic intervention. Studies of ALL have also led the way in dissecting the subclonal heterogeneity of cancer, and have shown that individual patients commonly harbor multiple related but genetically distinct subclones, and that this genetically determined clonal heterogeneity is an important determinant of relapse. In addition, genome-wide profiling has identified inherited genetic variants that influence ALL risk. Ongoing studies are deploying detailed integrative genetic transcriptomic and epigenetic sequencing to comprehensively define the genomic landscape of ALL. This review describes the recent advances in our understanding of the genetics of ALL, with an emphasis on those alterations of key pathogenic or therapeutic importance.

| S-EPMC3848419 | biostudies-literature

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration.

Project description:PurposeTo review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents.MethodsA review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups.ResultsWith long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome-positive, and Philadelphia chromosome-like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL.ConclusionThe information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL.

| S-EPMC4567699 | biostudies-literature

Proteogenomics of High hyperdiploid childhood acute lymphoblastic leukemia

Project description:Proteogenomic analysis and genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of High hyperdiploid childhood acute lymphoblastic leukemia.

2020-01-29 | MSV000084862 | MassIVE

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia.

Project description:BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination.

| S-EPMC6853288 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data