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Similarly, nanopore analysis performed in 6/16 patients with simultaneously detected mutations in codons Gly12 and Gln61 or Gly13 and Gln61 did not reveal any patients with the presence of these mutations together on the same I NRAS i gene's allele. Oncogenic mutations in the I NRAS i gene are carried by 10-22% acute myeloid leukemia (AML) patients and represent one of the most commonly detected molecular aberrations in AML [[1], [3], [5]]. There was no significant difference in CR rate (89.5% vs. 75.0%, I p i = 0.2109), OS (33 months vs. undefined, I p i = 0.4300) or EFS (10 vs. 9 months, I p i = 0.6191) between patients with single I NRAS i mutation vs. patients with multiple I NRAS i mutations, respectively. NGS results from 5/16 patients with simultaneously detected multiple point mutations in codons Gly12 and Gly13 did not reveal any patients carrying these mutations on the same I NRAS i gene's allele. [Extracted from the article]

Summary: Genetic mutations in acute myeloid leukaemia (AML) are assumed to occur in a sequential order; however, the predominant hierarchical roles of specific mutated genes have not been fully described. In this study, we aimed to determine the clonal involvement of the most frequent AML‐associated mutations. Using a targeted sequencing panel for 18 genes, we traced changes and relative clonal contribution of mutations in 52 patients. We analysed 35 pairs of diagnosis and relapse samples, 27 pairs of primary samples and corresponding patient‐derived xenografts, and 34 pairs of total leukocytes and corresponding isolated primitive cells or blast populations. In both relapse and xenografts, we observed conservation of main leukaemic clones and variability was limited to subclones with late‐acquired mutations. AML evolution thus mainly involved modification of subclones while the clonal background remained unchanged. NPM1 mutations were identified as the most probable leukaemia‐transformation lesion, remaining conserved in contrast to high variation of accompanying subclonal FLT3 and NRAS mutations. DNMT3A mutations represented the most stable mutations forming a preleukaemic background in most samples. Mutations in genes IDH1/2, TET2, RUNX1, ASXL1 and U2AF1 were detected both as preleukaemic and as subclonal lesions, suggesting a non‐specific order of acquisition. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed at analyzing the association of gene mutations and other acute myeloid leukemia (AML) characteristics with engraftment outcomes in immunodeficient mice and to select the engraftment outcomes that best reflect patient survival.Methods: Mutations in 19 genes as well as leukemia- and patient-related characteristics were analyzed for a group of 47 de novo AML samples with respect to three engraftment outcomes: engraftment ability, engraftment intensity (percentage of hCD45+ cells) and engraftment latency. Leukemia-related characteristics were additionally analyzed in an extended group of 68 samples that included the 47 de novo samples, and additional 21 samples from refractory and relapsed cases. Engraftment outcomes were compared with overall and event-free survival of the patients.Results: For the 47 de novo samples, no single mutation influenced engraftment, whereas the NPM1mut/DNMT3Amut co-mutation was associated with higher engraftment ability. NPM1mut/FLT3-ITDneg had lower engraftment intensity. Among leukemia-related characteristics, a complex karyotype was associated with higher engraftment intensity. Among patient-related characteristics, higher cytogenetic risk was associated with higher engraftment intensity, and failure to achieve clinical remission was associated with shorter engraftment latency. In the extended group of 68 samples, white blood count was associated with higher engraftment ability, and the presence of a complex karyotype was associated with higher engraftment intensity. Association with patient overall survival was seen only for engraftment intensity.Conclusions: The engraftment of AML was influenced by mutation-interactions and other AML characteristics, rather than by single mutated genes, and engraftment intensity best reflected clinical penetrance of AML. [ABSTRACT FROM AUTHOR]

The DNA methyl-transferase 3A gene (DNMT3A) is the third most frequently mutated gene in cytogenetically normal acute myeloid leukemia (CN-AML) patients (20-30 %), who belong to a group of patients with intermediate risk. About 60 % of mutations in this gene have been identified in the arginine codon R882. To date, there is no consensus on whether these mutations can be used as biomarkers for monitoring of minimal residual disease and management of preemptive AML therapy. We studied the occurrence of mutations in the DNMT3A gene in our cohort of patients and their persistence during AML treatment. Using next-generation sequencing, we identified four mutations in 11/25 of our analyzed patients--frequent R882C and R882H mutations, rare Y735S mutation, and a novel L347P mutation. Mutation R882C was detected in 5/11, R882H in 4/11 patients, and Y735S and L347P in one patient each. In 4/7 patients initially carrying mutations in the R882 codon, we found the persistence of mutations also during complete remission with, however, no correlation to AML kinetics. Our findings suggest that mutations in the DNMT3A gene can only be used as a biomarker for those AML patients in whom DNMT3A mutation is lost after therapy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented discussing a case of NPM1 gene mutation in a 19-year-old man diagnosed with with acute myeloid leukemia.

The nucleophosmin 1 ( NPM1) gene is one of the most commonly mutated genes in acute myeloid leukemia (AML), occurring in approximately 60% of adult cytogenetically normal AML (CN-AML). To date, these mutations have only been detected in cells of the myeloid lineage, whereas the potential clonal involvement of the lymphoid lineage is controversial. In our study, NPM1 mutations were analyzed using the highly sensitive real-time quantitative polymerase chain reaction (RQ-PCR) method on fluorescence-activated cell-sorted (FACS) purified different circulating mature cell populations in patients with NPM1-mutated CN-AML. As expected, NPM1 mutations were found in myeloid blood cells, including CD14+ monocytes and CD66b+ granulocytes. However, we were also able to detect NPM1 mutations in CD19+ B cells and CD3−14−16+56+ natural killer (NK) cells, albeit at lower levels. Surprisingly, mutations were also detected in CD3+ T cells from all analyzed patients. Our data demonstrate that NPM1-mutated CN-AML originates in an early stem cell with both lymphoid and myeloid differentiation potential. [ABSTRACT FROM AUTHOR]

The article discusses research which investigated isocitrate dehydrogenase (IDH) gene mutations in acute myeloid leukemia (AML) patients. Topics explored include the potential application of IDH2 mutation in minimal residual disease (MRD) monitoring, the analysis of bone marrow and peripheral blood samples collected from AML patients, and the patient characteristics recorded including nucleophosmin 1 (NPM1) gene mutation type and status.