Search results for "NPM"
showing 10 items of 26 documents
Focal Adhesion Genes Refine the Intermediate-Risk Cytogenetic Classification of Acute Myeloid Leukemia
2018
© 2018 by the authors.
All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07-0…
2016
The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18–60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m2, days 6–8; 15 mg/m2, days 9–21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred pati…
Differential expression of specific microRNA and their targets in acute myeloid leukemia
2010
Acute myeloid leukemia (AML) the most common acute leukemia in adults is characterized by various cytogenetic and molecular abnormalities. However, the genetic etiology of the disease is not yet fully understood. MicroRNAs (miRNA) are small noncoding RNAs which regulate the expression of target mRNAs both at transcriptional and translational level. In recent years, miRNAs have been identified as a novel mechanism in gene regulation, which show variable expression during myeloid differentiation. We studied miRNA expression of leukemic blasts of 29 cases of newly diagnosed and genetically defined AML using quantitative reverse transcription polymerase chain reaction (RT-PCR) for 365 human miR…
Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia.
2013
Mutations in the nucleophosmin 1 (NPM1) gene are considered a founder event in the pathogenesis of acute myeloid leukemia (AML). To address the role of clonal evolution in relapsed NPM1-mutated (NPM1mut) AML, we applied high-resolution, genome-wide, single-nucleotide polymorphism array profiling to detect copy number alterations (CNAs) and uniparental disomies (UPDs) and performed comprehensive gene mutation screening in 53 paired bone marrow/peripheral blood samples obtained at diagnosis and relapse. At diagnosis, 15 aberrations (CNAs, n = 10; UPDs, n = 5) were identified in 13 patients (25%), whereas at relapse, 56 genomic alterations (CNAs, n = 46; UPDs, n = 10) were detected in 29 patie…
Therapy-related acute myeloid leukemia developing 14 years after allogeneic hematopoietic stem cell transplantation, from a persistent R882H- DNMT3A …
2018
Abstract Background Therapy-related acute myeloid leukemia (t-AML) develops in patients with prior exposure to cytotoxic therapies. Selection of a pre-existing TP53 mutated clone prone to acquire additional mutational events has been suggested as the main pathogenic mechanism of t-AML. Here, we report a unique case of t-AML which developed from a pre-existing DNMT3A mutated clone that persisted in the patient for more than 10 years despite treatment with intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (alloHSCT). Case presentation A 42-year-old male was diagnosed with AML harboring a normal karyotype and mutations in the NPM1 (c.863_864ins, p.W288 fs*12), DNMT3…
DNMT3A mutations Predict for Inferior Outcome in NPM1-Wildtype and Molecular Unfavorable Cytogenetically-Normal Acute Myeloid Leukemia: A Study of th…
2011
Abstract Abstract 415 Background: Alteration of DNA methylation, a hallmark of epigenetic modification, is currently discussed as one important pathomechanism in leukemogenesis. Using a next-generation sequencing approach, a frameshift mutation of the gene encoding the DNA methyltransferase (DNMT3A) in an acute myeloid leukemia (AML) case was identified. DNMT3A catalyses the addition of a methyl group to the cytosine residue of CpG dinucleotides, thereby affecting promoter methylation status and gene expression. Subsequent sequencing analysis in an independent cohort of 288 AML patients (pts) revealed DNMT3A mutations (DNMT3Amut) in 22% of the pts; mutations were associated with intermediat…
Combined Targeting of the Menin-MLL1 Chromatin Complex and FLT3 As a Novel Therapeutic Concept Against NPM1 Mutant or MLL-Rearranged AML with Mutated…
2019
NPM1mutant (NPM1mut) and MLL1-rearranged (MLL-r) acute myeloid leukemias (AMLs) exhibit aberrant expression of HOX and MEIS1 transcription factors and commonly harbor an activating mutation in the receptor tyrosine kinase FLT3. Pharmacologic inhibition of the menin-MLL1 complex reverses leukemogenic gene expression including MEIS1 and FLT3 and represents a therapeutic opportunity for the treatment of these leukemias. Here, we investigate the contribution of the menin-MLL1 complex to leukemic FLT3 signaling and assess the therapeutic potential of dual menin-MLL1 and FLT3 targeting. First, we performed RNA sequencing to delineate transcriptional changes associated with menin-MLL1 inhibition (…
Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition
2020
Abstract The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and provides a potential opportunity for treatment of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. In this study, transcriptional profiling after pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expression, with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being the most pronounced. Combining menin-MLL inhibition with specific small-molecule kinase inhibitors…
Ny arbeids- og velferdsforvaltning : oppretting av NAV-kontorer i kommunene : rapport fra en pilotstudie høsten 2006
2006
1.juli 2006 ble den Nye Arbeids- og Velferdsforvaltning opprettet. Det er den største omorganisering som er skjedd innen velferdstjenesteområdet i Norge noen gang. 16000 ansatte er involvert og alle landets kommuner blir engasjert i denne. For å få en oversikt over reformen og over området som endres ble denne rapporten laget. Rapporten er derfor en beskrivende rapport både når det gjelder fortid om hvordan de tidligere etatene ble til og fungerte og når det gjelder nåsituasjonen for reformen. Fortiden beskrives i en gjennomgang av historien bak, mens nåsituasjonen beskrives dels ved en gjennomgang av reformens ulike dokumenter og ved svarene som fremkom i en intervjurunde foretatt i forhol…
Prognostic Impact of Mutant to Wild-Type Ratio and Insertion Site in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication
2012
Abstract Abstract 785 Background: FLT3 internal tandem duplications (FLT3-ITD) occur in about 25% of acute myeloid leukemia (AML), are associated with cooperating gene mutations (NPM1, DNMT3A), and confer an adverse prognosis. Several studies have indicated that the unfavorable impact of FLT3-ITD is influenced by a number of factors, such as the mutant to wild-type ratio (allelic ratio), insertion site of FLT3-ITD in the beta1 sheet of the tyrosine kinase domain 1, and the molecular background of cooperating mutations. Aims: To evaluate the relative impact of FLT3-ITD allelic ratio and insertion site, as well as cooperating genetic lesions on prognosis and treatment decision making in a lar…