Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

University Hospital of Ulm, Ulm, Germany.
New England Journal of Medicine (Impact Factor: 55.87). 06/2008; 358(18):1909-18. DOI: 10.1056/NEJMoa074306
Source: PubMed


Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein alpha gene (CEPBA), the myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these mutations with clinical outcomes in patients.
We compared the mutational status of the NPM1, FLT3, CEBPA, MLL, and NRAS genes in leukemia cells with the clinical outcome in 872 adults younger than 60 years of age with cytogenetically normal AML. Patients had been entered into one of four trials of therapy for AML. In each study, patients with an HLA-matched related donor were assigned to undergo stem-cell transplantation.
A total of 53% of patients had NPM1 mutations, 31% had FLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosine kinase-domain mutations, 13% had CEBPA mutations, 7% had MLL partial tandem duplications (PTDs), and 13% had NRAS mutations. The overall complete-remission rate was 77%. The genotype of mutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, and younger age were each significantly associated with complete remission. Of the 663 patients who received postremission therapy, 150 underwent hematopoietic stem-cell transplantation from an HLA-matched related donor. Significant associations were found between the risk of relapse or the risk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD (hazard ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), the mutant CEBPA genotype (hazard ratio, 0.48; 95% CI, 0.30 to 0.75), and the MLL-PTD genotype (hazard ratio, 1.56; 95% CI, 1.00 to 2.43), as well as receipt of a transplant from an HLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44 to 0.82). The benefit of the transplant was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD.
Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML.

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    • "Moreover, the NPM1-positive/FLT3-ITD-negative AML patients did not benefit from allogeneic stem cell transplantation. The opposite conclusions have been drawn for patients with mutant FLT3-ITD and wild-type NPM1 and CEBPA without FLT3-ITD [11]. It was also found that AML patients with the presence of NPM1 mutation at diagnosis still had this abnormality at relapse. "
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    ABSTRACT: Aim of the study Mutant NPM1 and CEBPA have been reported in patients with acute myeloid leukaemia (AML) and intermediate cytogenetic risk, and they appear to be associated with characteristic demographic and laboratory data, as well as clinical outcome. The objective of the study was to assess the clinical relevance of NPM1 and CEBPA mutations in AML. Material and methods This retrospective analysis was based on 60 newly diagnosed patients with AML and normal/no metaphases karyotype and known mutation status, who were treated in our centre between 2008 and 2011 according to the PALG (Polish Adult Leukaemia Group) study protocol. Pretreatment bone marrow samples were studied by G-banding analysis, and NPM1, CEBPA, and FLT3-ITD mutations were detected by polymerase chain reaction (PCR). Results NPM1 mutations were detected in 21 AML patients (35%). In the NPM1-positive subgroup, the FLT3-ITD mutation was observed in 3 cases (14%), which was significantly less frequent than in the NPM1-negative patients, where FLT3-ITD was detected in 16 cases (41%; p = 0.04). Among the CEBPA-positive population (n = 11; 18%), none of the studied patients had FLT3-ITD mutation, whereas it was detected in 19 CEBPA-negative patients (0% vs. 38%; p = 0.01). The highest complete remission rate was reported for the NPM1-positive/FLT3-ITD-negative group (n = 18; 88%) and the CEBPA-positive/FLT3-ITD-negative group (n = 8; 73%). For OS, multivariable analysis revealed NPM1-positive/FLT3-ITD-negative (HR: 0.18, 95% CI: 0.19–0.63) and CEBPA-positive/FLT3-ITD-negative (HR: 0.35, 95% CI: 0.19–0.63) as favourable prognostic factors. The presence of the NPM1-negative/FLT3-ITD-positivecombination predicted adverse overall survival (HR: 2.03, 95% CI: 1.13–3.66). Conclusions NPM1 and CEBPA mutations are associated with clinical outcome in AML patients.
    Full-text · Article · Aug 2014 · Contemporary Oncology / Wspólczesna Onkologia
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    • "RUNX1-RUNX1T1, PML-RARα, DEK-NUP214, CBFβ-MYH11) [21] and mutations of clinically relevant genes (e.g. NPM1, CEBPα, FLT3, c-KIT) [17-22]. Unfortunately, approximately half of AML patients lack a molecular target suitable for MRD monitoring [23]. "
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    ABSTRACT: Background In acute myeloid leukemia (AML), the MDS1 and EVI1 complex locus - MECOM, also known as the ecotropic virus integration site 1 - EVI1, located in band 3q26, can be rearranged with a variety of partner chromosomes and partner genes. Here we report on a 57-year-old female with AML who presented with the rare translocation t(3;10)(q26;q21) involving the MECOM gene. Our aim was to identify the fusion partner on chromosome 10q21 and to characterize the precise nucleotide sequence of the chromosomal breakpoint. Methods Cytogenetic and molecular-cytogenetic techniques, chromosome microdissection, next generation sequencing, long-range PCR and direct Sanger sequencing were used to map the chromosomal translocation. Results Using a combination of cytogenetic and molecular approaches, we mapped the t(3;10)(q26;q21) to the single nucleotide level, revealing a fusion of the MECOM gene (3q26.2) and C10orf107 (10q21.2). Conclusions The approach described here opens up new possibilities in characterizing acquired as well as congenital chromosomal aberrations. In addition, DNA sequences of chromosomal breakpoints may be a useful tool for unique molecular minimal residual disease target identification in acute leukemia patients.
    Full-text · Article · Jul 2014 · Molecular Cytogenetics
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    • "Reduced CEBPA expression or loss of function mutations are commonly observed in AML suggesting that the deregulation of CEBPA function is a major event in the development of AML181920. Identifying new CEBPA target genes and associated CEBPA-dependent pathways in myeloid differentiation may provide novel insights into the differentiation block as well as into ancillary cellular functions found in AML. Interestingly, CEBPA has been described as a pivotal regulator of various metabolic processes in different cell types21. "
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    ABSTRACT: The basic leucine zipper transcription factor CCAAT/enhancer binding protein alpha (CEBPA) codes for a critical regulator during neutrophil differentiation. Aberrant expression or function of this protein contributes to the development of acute myeloid leukemia (AML). In this study, we identified two novel unrelated CEBPA target genes, the glycolytic enzyme hexokinase 3 (HK3) and the krüppel-like factor 5 (KLF5) transcription factor, by comparing gene profiles in two cohorts of CEBPA wild-type and mutant AML patients. In addition, we found CEBPA-dependent activation of HK3 and KLF5 transcription during all-trans retinoic acid (ATRA) mediated neutrophil differentiation of acute promyelocytic leukemia (APL) cells. Moreover, we observed direct regulation of HK3 by CEBPA, whereas our data suggest an indirect regulation of KLF5 by this transcription factor. Altogether, our data provide an explanation for low HK3 and KLF5 expression in particular AML subtype and establish these genes as novel CEBPA targets during neutrophil differentiation.
    Full-text · Article · Mar 2014 · Scientific Reports
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