Browse
Submit Data
Databases
API
Help

Dataset Information

34 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

How I treat pediatric acute myeloid leukemia.

ABSTRACT: Acute myeloid leukemia is a heterogeneous disease that accounts for approximately 20% of acute leukemias in children and adolescents. Despite the lack of targeted therapy for most subtypes and a dearth of new agents, survival rates have reached approximately 60% for children treated on clinical trials in developed countries. Most of the advances have been accomplished by better risk classification, the implementation of excellent supportive care measures, adaptation of therapy on the basis of each patient's response to therapy, and improvements in allogeneic hematopoietic stem cell transplantation. However, it is unlikely that further gains can be made through these measures alone. In this regard, high-resolution, genome-wide analyses have led to greater understanding of the pathogenesis of this disease and the identification of molecular abnormalities that are potential targets of new therapies. The development of molecularly targeted agents, some of which are already in clinical trials, holds great promise for the future.

SUBMITTER: Rubnitz JE

PROVIDER: S-EPMC3383013 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

How I treat pediatric acute myeloid leukemia.

Rubnitz Jeffrey E JE

Blood 20120507 25

Acute myeloid leukemia is a heterogeneous disease that accounts for approximately 20% of acute leukemias in children and adolescents. Despite the lack of targeted therapy for most subtypes and a dearth of new agents, survival rates have reached approximately 60% for children treated on clinical trials in developed countries. Most of the advances have been accomplished by better risk classification, the implementation of excellent supportive care measures, adaptation of therapy on the basis of ea ...[more]

PMID: 22566607

Similar Datasets

How I treat acute myeloid leukemia presenting with preexisting comorbidities.

Project description:Acute myeloid leukemia (AML) is a devastating disease with an incidence that progressively increases with advancing age. Currently, only ∼40% of younger and 10% of older adults are long-term survivors. If untreated, the overall prognosis of AML remains dismal. Initiation of therapy at diagnosis is usually urgent. Barriers to successful therapy for AML are the attendant toxicities directly related to chemotherapy or those associated with inevitable aplasia. Organ dysfunction often further complicates such toxicities and may even be prohibitive. There are few guidelines to manage such patients and the fear of crossing the medico-legal abyss may dominate. Such clinical scenarios provide particular challenges and require experience for optimal management. Herein, we discuss select examples of common pretreatment comorbidities, including cardiomyopathy, ischemic heart disease; chronic renal failure, with and without dialysis; hepatitis and cirrhosis; chronic pulmonary insufficiency; and cerebral vascular disease. These comorbidities usually render patients ineligible for clinical trials and enormous uncertainty regarding management reigns, often to the point of withholding definitive therapy. The scenarios described herein emphasize that with appropriate subspecialty support, many AML patients with comorbidities can undergo therapy with curative intent and achieve successful long-term outcome.

| S-EPMC5524532 | biostudies-other

How to Treat Adult Acute Myeloid Leukemia : An Evolving Paradigm

Project description: Not available

| S-EPMC8702813 | biostudies-literature

Molecular therapeutic approaches for pediatric acute myeloid leukemia.

Project description:Approximately two-thirds of children with acute myeloid leukemia (AML) are cured with intensive multi-agent chemotherapy. However, refractory and relapsed AML remains a significant source of childhood cancer mortality, highlighting the need for new therapies. Further therapy intensification with traditional cytotoxic chemotherapy in pediatric AML is not feasible given the risks of both short-term and long-term organ dysfunction. Substantial emphasis has been placed upon the development of molecularly targeted therapeutic approaches for adults and children with high-risk subtypes of AML with the goal of improving remission induction and minimizing relapse. Several promising agents are currently in clinical testing or late preclinical development for AML, including monoclonal antibodies against leukemia cell surface proteins, kinase inhibitors, proteasome inhibitors, epigenetic agents, and chimeric antigen receptor engineered T cell immunotherapies. Many of these therapies have been specifically tested in children with relapsed/refractory AML in Phase 1 and 2 trials with a smaller number of new agents under Phase 3 evaluation for children with de novo AML. Although successful identification and implementation of new drugs for children with AML remain a formidable challenge, enthusiasm for novel molecular therapeutic approaches is great given the potential for significant clinical benefit for children who do not have other curative options.

| S-EPMC3957536 | biostudies-literature

Direct and indirect targeting of MYC to treat acute myeloid leukemia.

Project description:Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is often resistant to conventional therapies. The MYC oncogene is commonly overexpressed in AML but has remained an elusive target. We aimed to examine the consequences of targeting MYC both directly and indirectly in AML overexpressing MYC/Myc due to trisomy 8/15 (human/mouse), FLT3-ITD mutation, or gene amplification.We performed in vivo knockdown of Myc (shRNAs) and both in vitro and in vivo experiments using four drugs with indirect anti-MYC activity: VX-680, GDC-0941, artemisinin, and JQ1.shRNA knockdown of Myc in mice prolonged survival, regardless of the mechanism underlying MYC overexpression. VX-680, an aurora kinase inhibitor, demonstrated in vitro efficacy against human MYC-overexpressing AMLs regardless of the mechanism of MYC overexpression, but was weakest against a MYC-amplified cell line. GDC-0941, a PI3-kinase inhibitor, demonstrated efficacy against several MYC-overexpressing AMLs, although only in vitro. Artemisinin, an antimalarial, did not demonstrate consistent efficacy against any of the human AMLs tested. JQ1, a bromodomain and extra-terminal bromodomain inhibitor, demonstrated both in vitro and in vivo efficacy against several MYC-overexpressing AMLs. We also confirmed a decrease in MYC levels at growth inhibitory doses for JQ1, and importantly, sensitivity of AML cell lines to JQ1 appeared independent of the mechanism of MYC overexpression.Our data support growing evidence that JQ1 and related compounds may have clinical efficacy in AML treatment regardless of the genetic abnormalities underlying MYC deregulation.

| S-EPMC4485702 | biostudies-literature

Leukemia Stem Cell Release From the Stem Cell Niche to Treat Acute Myeloid Leukemia.

Project description:Acute myeloid leukemia (AML) is a heterogeneous, complex, and deadly disease, whose treatment has hardly evolved for decades and grounds on the use of intensive chemotherapy regimens. Chemotherapy helps reduce AML bulk, but promotes relapse in the long-run by selection of chemoresistant leukemia stem cells (LSC). These may diversify and result in progression to more aggressive forms of AML. In vivo models suggest that the bone marrow stem cell niche helps LSC stay dormant and protected from chemotherapy. Here, we summarize relevant changes in stem cell niche homing and adhesion of AML LSC vs. healthy hematopoietic stem cells, and provide an overview of clinical trials aiming at targeting these processes for AML treatment and future directions within this field. Promising results with various non-mutation-targeted novel therapies directed to LSC eradication via interference with their anchoring to the stem cell niche have encouraged on-going or future advanced phase III clinical trials. In the coming years, we may see a shift in the focus of AML treatment to LSC-directed therapies if the prospect of improved cure rates holds true. In the future, AML treatment should lean toward personalized therapies using combinations of these compounds plus mutation-targeted agents and/or targeted delivery of chemotherapy, aiming at LSC eradication with reduced side effects.

| S-EPMC7367216 | biostudies-literature

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia.

Project description:IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations using direct sequencing. Three patients were identified with a single amino acid variant without change of IKZF1 length. No frame-shift mutations were found. Out of 11 patients with an IKZF1 deletion, 8 samples revealed a complete loss of chromosome 7, and 3 cases a focal deletion of 0.1-0.9Mb. These deletions included the complete IKZF1 gene (n=2) or exons 1-4 (n=1), all leading to a loss of IKZF1 function. Interestingly, differentially expressed genes in monosomy 7 cases (n=8) when compared to non-deleted samples (n=247) significantly correlated with gene expression changes in focal IKZF1-deleted cases (n=3). Genes with increased expression included genes involved in myeloid cell self-renewal and cell cycle, and a significant portion of GATA target genes and GATA factors. Together, these results suggest that loss of IKZF1 is recurrent in pediatric acute myeloid leukemia and might be a determinant of oncogenesis in acute myeloid leukemia with monosomy 7.

| S-EPMC4800704 | biostudies-literature

Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia.

Project description:Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide. The focus is on translational and clinical research, which includes past, current, and future clinical trials. Separate sections concern acute promyelocytic leukemia, myeloid leukemia of Down syndrome, and relapsed AML. A plethora of novel antileukemic agents that have emerged, including new classes of drugs, are summarized as well. Finally, an important aspect of the treatment of pediatric AML--supportive care--and late effects are discussed. The future is bright, with a wide range of emerging innovative therapies and with more and more international collaboration that ultimately aim to cure all children with AML, with fewer adverse effects and without late effects.

| S-EPMC4567700 | biostudies-literature

BCOR and BCORL1 mutations in pediatric acute myeloid leukemia.

Project description: Not available

| S-EPMC4420230 | biostudies-literature

Clinicopathological Implications of Mitochondrial Genome Alterations in Pediatric Acute Myeloid Leukemia.

Project description:To the best of our knowledge, the association between pediatric AML and mitochondrial aberrations has not been studied. We investigated various mitochondrial aberrations in pediatric AML and evaluated their impact on clinical outcomes.Sequencing, mitochondrial DNA (mtDNA) copy number determination, mtDNA 4,977-bp large deletion assessments, and gene scan analyses were performed on the bone marrow mononuclear cells of 55 pediatric AML patients and on the peripheral blood mononuclear cells of 55 normal controls. Changes in the mitochondrial mass, mitochondrial membrane potential, and intracellular reactive oxygen species (ROS) levels were also examined.mtDNA copy numbers were about two-fold higher in pediatric AML cells than in controls (P<0.0001). Furthermore, a close relationship was found between mtDNA copy number tertiles and the risk of pediatric AML. Intracellular ROS levels, mitochondrial mass, and mitochondrial membrane potentials were all elevated in pediatric AML. The frequency of the mtDNA 4,977-bp large deletion was significantly higher (P<0.01) in pediatric AML cells, and pediatric AML patients harboring high amount of mtDNA 4,977-bp deletions showed shorter overall survival and event-free survival rates, albeit without statistical significance.The present findings demonstrate an association between mitochondrial genome alterations and the risk of pediatric AML.

| S-EPMC4713842 | biostudies-other

Classification of pediatric acute myeloid leukemia based on miRNA expression profiles.

Project description:Pediatric acute myeloid leukemia (AML) is a heterogeneous disease with respect to biology as well as outcome. In this study, we investigated whether known biological subgroups of pediatric AML are reflected by a common microRNA (miRNA) expression pattern. We assayed 665 miRNAs on 165 pediatric AML samples. First, unsupervised clustering was performed to identify patient clusters with common miRNA expression profiles. Our analysis unraveled 14 clusters, seven of which had a known (cyto-)genetic denominator. Finally, a robust classifier was constructed to discriminate six molecular aberration groups: 11q23-rearrangements, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17) (q21;q22), NPM1 and CEBPA mutations. The classifier achieved accuracies of 89%, 95%, 95%, 98%, 91% and 96%, respectively. Although lower sensitivities were obtained for the NPM1 and CEBPA (32% and 66%), relatively high sensitivities (84%-94%) were attained for the rest. Specificity was high in all groups (87%-100%). Due to a robust double-loop cross validation procedure employed, the classifier only employed 47 miRNAs to achieve the aforementioned accuracies. To validate the 47 miRNA signatures, we applied them to a publicly available adult AML dataset. Albeit partial overlap of the array platforms and molecular differences between pediatric and adult AML, the signatures performed reasonably well. This corroborates our claim that the identified miRNA signatures are not dominated by sample size bias in the pediatric AML dataset. In conclusion, cytogenetic subtypes of pediatric AML have distinct miRNA expression patterns. Reproducibility of the miRNA signatures in adult dataset suggests that the respective aberrations have a similar biology both in pediatric and adult AML.

| S-EPMC5464851 | biostudies-other

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