• genes
  • The study succeeded because it combined the field of gene mutation research and the new field of epigenetics, which identifies genes silenced by faulty DNA methylation, says Christoph Plass, professor of molecular virology, immunology and medical genetics and of veterinary biosciences, and also co-principal investigator on the study. (eurekalert.org)
  • Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (CML) are rare hematologic neoplasms that are characterized by leukocytosis and hypercellularity of bone marrow consisting predominantly of granulocytic cells, the absence of the Philadelphia chromosome with translocation t(9;22) ( BCR-ABL1 ), and the absence of rearrangements in genes encoding plateletderived growth factor receptors alpha and beta ( PDGFRA/B ) and fibroblast growth factor receptor 1 ( FGFR1 ). (pubmedcentralcanada.ca)
  • We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. (aacrjournals.org)
  • This gene is frequently mutated in cancer, being one of 127 frequently mutated genes identified in the Cancer Genome Atlas project DNMT3A mutations were most commonly seen in acute myeloid leukaemia (AML) where they occurred in just over 25% of cases sequenced. (wikipedia.org)
  • Inactivating mutations of acetyltransferase genes in B-cell lymphoma. (wikipedia.org)
  • The RUNX1 and CBFB genes are targets of chromosome rearrangements that create oncogenic fusion genes in leukemia. (wikipedia.org)
  • The chromosome translocation t(12;21) (p13.1;q22) causes the fusion of the ETS variant 6 (ETV6) and RUNX1 genes results in ETV6-RUNX1 gene fusion and is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL). (wikipedia.org)
  • DNMT3A
  • Although genetic changes previously were found in AML, this work shows that newly discovered mutations in a single gene, called DNA methyltransferase 3A or DNMT3A , appear responsible for treatment failure in a significant number of AML patients. (genome.gov)
  • In the study, the researchers found DNMT3A mutations in 21 percent of all AML patients studied and in 34 percent of the patients classified as having an intermediate risk of treatment failure based on widely used laboratory tests of their leukemia cells. (genome.gov)
  • For patients with the DNMT3A mutation, however, chemotherapy may not be the best first treatment. (genome.gov)
  • In the cases we studied, mutations in the DNMT3A gene trump everything else we've found so far to predict adverse outcomes in intermediate-risk AML. (genome.gov)
  • Based on what we found, if a patient has a DNMT3A mutation, it looks like you're going to want to treat very aggressively, perhaps go straight to bone marrow transplantation or a more intensive chemotherapy regimen," says senior author Richard K. Wilson, Ph.D., director of Washington University's Genome Center. (genome.gov)
  • Those with DNMT3A mutations treated with bone marrow transplants lived longer than those who received only chemotherapy, but the Washington University investigators caution that the sample size was small and follow-up studies will be needed to confirm these initial findings. (genome.gov)
  • DNMT3A mutations are associated with poor overall survival, suggesting that they have an important common effect on the potential of AML cells to cause lethal disease. (wikipedia.org)
  • somatic mutations
  • The establishment of a clonal population may occur when a stem or progenitor cell acquires one or more somatic mutations that give it a competitive advantage in hematopoiesis over the stem/progenitor cells without these mutations. (wikipedia.org)
  • The advent of next-generation DNA sequencing has allowed for the targeted identification of somatic mutations involved in clonal hematopoiesis at the population level. (wikipedia.org)
  • novel
  • Using whole-exome sequencing and trio-based de novo analysis, we identified a novel heterozygous de novo frameshift variant in the leukemia inhibitory factor receptor (LIFR) gene causing instability of the mRNA in a patient presenting with bilateral CAKUT and requiring kidney transplantation at one year of age. (sigmaaldrich.com)
  • Altogether, we demonstrate heterozygous novel or rare LIFR mutations in 3.3% of CAKUT patients, and provide evidence that Lifr deficiency and deactivating LIFR mutations cause highly similar anomalies of the urogenital tract in mice and humans. (sigmaaldrich.com)
  • HHMI researchers used a novel recruitment strategy to identify patients who helped them pinpoint the genetic malfunctions that cause three different forms of leukemia. (hhmi.org)
  • Recently, a novel form of abnormality in acute myeloid leukemia (AML), uniparental disomy, has been revealed through the application of single nucleotide polymorphism (SNP) genotype array technology ( 1 ). (aacrjournals.org)
  • In order to assess the ability of these mutations to lead to novel inhibitor schemes, the functional impact of each mutation was analyzed through robust structure function methods. (columbia.edu)
  • Most notably, the majority of NT5C2 mutations identified have characteristics that suggest they abrogate the function of this proposed mechanism, yielding a novel viable target for the development of allosteric inhibitors specific for constitutively active NT5C2 mutant proteins. (columbia.edu)
  • Overall, these findings validate inhibition of RUNX1- CBFβ-SMMHC protein-protein interaction as a novel therapeutic avenue for leukemia with inv(16) and AI-10-49 as a specific inhibitor of CBFβ-SMHHC oncoprotein. (wikipedia.org)
  • researchers
  • Researchers identified the mutation by testing a family in which the father, four sons, a grandson and a distant female relative developed this form of leukemia. (eurekalert.org)
  • In 2005, other Ohio State Comprehensive Cancer Center researchers discovered a germline mutation in a gene for a microRNA that is implicated in CLL, suggesting that this may also be a predisposing mutation for the disease. (eurekalert.org)
  • Washington, Apr 4 (ANI): Researchers have identified a mutation in a gene called DDR2 that may indicate which patients with squamous cell lung cancer will respond to a leukemia drug called dasatinib. (thaindian.com)
  • The research published today was focused on better understanding the lab's model system, to ensure that future researchers trying to identify cancer-causing mutations are using accurate and reproducible methods. (technologynetworks.com)
  • Most of the hundreds of mutations found in acute myeloid leukemia (AML) genomes occur randomly as part of the aging process, independent of the development of cancer, researchers have found. (oncologynurseadvisor.com)
  • This knowledge can help researchers zero in on the few mutations that may eventually respond to targeted therapy. (oncologynurseadvisor.com)
  • Three leukemias that affect as many as 100,000 people in the United States are all caused by acquired mutations that alter a specific enzyme controlling blood cell proliferation, according to new studies by Howard Hughes Medical Institute (HHMI) researchers. (hhmi.org)
  • Identifying the genetic malfunction that causes these disorders raises the hope that researchers may be able to devise a targeted therapy, just as they have done for chronic myelogenous leukemia (CML), which is presently treated with Gleevec. (hhmi.org)
  • By comparing the DNA sequences from the blood with those from the mouth swabs, the researchers could determine which mutations the blood cell progenitors had acquired-since the mouth-swab DNA represents inherited germline DNA that had not undergone mutation. (hhmi.org)
  • And since the researchers did not find the mutation in a large number of normal blood samples, they were able to conclude that the mutation was characteristic of a large fraction of the three leukemias. (hhmi.org)
  • Researchers at The Hospital for Sick Children (SickKids) have shown for the first time how mutations in the ETV6 gene, that increase the risk of developing leukemia, can also interfere with production of platelets (blood cells responsible for clotting). (sickkids.ca)
  • It has been known for some time that when ETV6 is mutated in bone marrow cells there is an increased risk of childhood leukemia, which led researchers to describe ETV6 as a cancer-suppressor gene. (sickkids.ca)
  • cancers
  • Using standard genetic sequencing techniques, Meyerson and colleagues identified mutations in the DDR2 kinase gene in about 3 percent of squamous cell lung cancers and cell lines. (thaindian.com)
  • These findings, which were published in the journal Cell ( 2012;150:264-278 ), help to explain why leukemia becomes more common with age (AML is relatively uncommon until about the age of 60 years), and could explain the large numbers of mutations found in breast, lung, and other cancers. (oncologynurseadvisor.com)
  • NT5C2
  • Using next-generation sequencing to compare the genomes of tumors before and after therapy, mutations in gene cytosolic 5'-nucleotidase II (NT5C2) were discovered in 19% of pediatric samples with relapsed T-ALL(Tzoneva, Carpenter et al. (columbia.edu)
  • Overall these findings support a prominent role for activating mutations in NT5C2 and chemotherapy resistance in ALL, and highlight new avenues for relapsed ALL therapy development in the future. (columbia.edu)
  • Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. (wikipedia.org)
  • clinical
  • A patient whose cancer carried a DDR2 mutation also showed a clinical response to dasatinib. (thaindian.com)
  • A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib. (pubmedcentralcanada.ca)
  • The detection of point mutations in a background of wild-type transcripts will provide substantial benefits for diagnostic and prognostic testing and clinical management of these diseases. (sbir.gov)
  • The availability of this assay for leukemia and MPD mutations should greatly improve the clinical decisions necessary for effective treatment of leukemia and MPD patients while improving clinical laboratory workflow and reducing costs. (sbir.gov)
  • Recently, several independent studies have confirmed the presence of malignancy-associated mutations in the blood of individuals who have no clinical signs of hematologic malignancy. (wikipedia.org)
  • myeloproliferative disorders
  • Abstract DESCRIPTION (provided by applicant): The overall objective for this project is to develop a diagnostic assay for rapid detection of major mutations in patients with acute myeloid leukemia (AML), non-BCR/ABL chronic myelogenous leukemia (CML) and myeloproliferative disorders (MPDs). (sbir.gov)
  • The overall goal of this proposal is to develop an assay to detect mutations that are important for determining treatment of myeloproliferative disorders and leukemia. (sbir.gov)
  • This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders. (aacrjournals.org)
  • distinct
  • These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. (pubmedcentralcanada.ca)
  • The latest WHO classification (2008, Lyon), classifies Acute Myeloid Leukemia into distinct subtypes, based on clinico-pathological and molecular features. (wikipedia.org)
  • malignancy
  • In many cases, only one or two additional, cooperating mutations are needed to generate the malignancy. (oncologynurseadvisor.com)
  • The combination of these two ideas, that clonal hematopoiesis might be common in the elderly population and that AML evolves from pre-leukemic populations, led to the hypothesis that malignancy-associated mutations could also contribute to asymptomatic clonal hematopoiesis in healthy individuals. (wikipedia.org)
  • This view gained mechanistic support in 2012 when it was found a number of the women who showed evidence for clonal hematopoiesis through X-inactivation skew also had mutations in the hematologic-malignancy-associated gene TET2. (wikipedia.org)
  • acquires
  • Upon further investigation involving the isolation of blood stem cells from healthy people ranging from newborns to a man in his 70s, Link's team discovered that each of the approximately 10,000 blood stem cells in a person's bone marrow acquires about 10 mutations over the course of a year, so that by age 50 years, nearly 500 mutations have accrued in every blood stem cell. (oncologynurseadvisor.com)
  • clonal
  • Alternatively, clonal hematopoiesis may arise without a driving mutation, through mechanisms such as neutral drift in the stem cell population. (wikipedia.org)
  • Importantly, these findings described an increase in this nonrandom skewing with increasing age, hinting that unobserved mutations acquired with age could be driving a clonal expansion. (wikipedia.org)
  • In a similar vein, other studies using the HUMARA technology had found that hematologic malignancies are clonal diseases even when there is no apparent chromosomal abnormality, and that there are pre-leukemic clonal populations which precede acute myeloid leukemia (AML). (wikipedia.org)
  • molecular pathogenesis
  • As the molecular pathogenesis for these diseases is becoming evident, and mutation-specific inhibitors become available, classification will need to include molecular identification. (sbir.gov)
  • bone
  • The research demonstrated how mutant ETV6 exerts its effects in megakaryocytes (bone marrow cells that give rise to platelets) and most likely in other bone marrow cells involved in leukemia. (sickkids.ca)
  • Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cells. (wikipedia.org)
  • The underlying mechanism involves replacement of normal bone marrow with leukemia cells, which results in a drop in red blood cells, platelets, and normal white blood cells. (wikipedia.org)
  • platelet
  • In a collaborative effort, research teams led by Dr. Walter Kahr at SickKids and Drs. Jorge Di Paola and Christopher Porter at the University of Colorado used a wide-ranging genetic screen involving families in the United States and across Europe to identify two hereditary ETV6 mutations associated with increased leukemia susceptibility and low platelet counts. (sickkids.ca)
  • Animal studies also linked ETV6 mutations to decreased platelet production. (sickkids.ca)
  • But it was not known how ETV6 mutations influenced cancer susceptibility and platelet development. (sickkids.ca)
  • This study makes connections between inherited ETV6 mutations, cancer and platelet development in humans. (sickkids.ca)
  • Point-mutations in RUNX1 gene have been reported in patients with familial platelet disorder, myeloid dysplastic syndrome, and chronic myelomonocytic leukemia. (wikipedia.org)
  • protein
  • Of high importance is NPM involvement in acute myelogenous leukemia, where a mutated protein lacking a folded C-terminal domain (NPM1c+) has been found in the cytoplasm in patients This aberrant localization has been linked to the development of the disease. (wikipedia.org)
  • Strategies against this subtype of acute myelogenous leukemia include the refolding of the C-terminal domain using pharmalogical chaperones and the displacement of the protein from nucleolus to nucleoplasm, which has been linked to apoptotic mechanisms. (wikipedia.org)
  • Congenital sucrase-isomaltase deficiency (CSID), also called genetic sucrase-isomaltase deficiency (GSID), and sucrose intolerance, is a genetic, intestional disorder that is caused by a reduction or absence of sucrase and isomaltase Explanations for GSID include: Mutations C1229Y and F1745C, which are present in the sucrase domain of SI, block SI path to anchor in the cell's aprical membrane but does not impact protein folding or isomaltase activity. (wikipedia.org)
  • findings
  • The findings could help identify people at risk for chronic leukemia, but they also may provide new insights into the process of natural cell death. (eurekalert.org)
  • chromosomal
  • Other chemotherapy agents, specifically epipodophyllotoxins and anthracyclines, have also been associated with treatment-related leukemias, which are often associated with specific chromosomal abnormalities in the leukemic cells. (wikipedia.org)
  • subset
  • Just as the observation of the same DNA mutation in a subset of cells suggests a single founding source, this X-inactivation skew suggests that a greater than expected number of cells are being generated from the same precursor. (wikipedia.org)
  • Reagents
  • The final outcome is to launch mutation-specific Analyte Specific Reagents (primers, probes) and apply for FDA approval as an In Vitro Diagnostic Assay. (sbir.gov)
  • melanoma
  • Mutations which change amino acid residues 12, 13 or 61 activate the potential of N-ras to transform cultured cells and are implicated in a variety of human tumors e.g. melanoma. (wikipedia.org)
  • Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma McCormick F (1996). (wikipedia.org)
  • patient
  • His initial research, identifying and characterizing a growth-activating mutation in a patient with T-cell leukemia, was first published last April in the journal Leukemia. (technologynetworks.com)
  • Then we had the question: 'Did the cells transform because of a mutation the patient had, or did they transform because these new mutations they managed to pick up somewhere? (technologynetworks.com)
  • Additionally, a form of cryptorchidism was detected in all Lifr-/- mice and the patient carrying the LIFR frameshift mutation. (sigmaaldrich.com)
  • The Washington University School of Medicine in St. Louis team initially discovered a mutation by completely sequencing the genome of a single AML patient. (genome.gov)
  • They then used targeted DNA sequencing on nearly 300 additional AML patient samples to confirm that mutations discovered in one gene correlated with the disease. (genome.gov)
  • cases
  • CLL is the most common form of adult leukemia, with 15,300 new cases and 4,500 deaths from the disease expected this year in the United States. (eurekalert.org)
  • According to the American Cancer Society, 34,800 new cases of all types of leukemia were reported in the US in 2005. (sbir.gov)
  • One third of cases is associated with a t(1;22)(p13;q13) mutation in children. (wikipedia.org)
  • cells
  • Our DNA can tolerate a huge number of these hits without any negative consequences, but if a cancer-initiating event occurs in one of these stem cells, it captures the genetic history of that cell, including the earlier mutations, and drives leukemia to develop. (oncologynurseadvisor.com)
  • They then set out to determine how these mutations affect cells. (sickkids.ca)