Among patients with acute myeloid leukemia, gene sequencing during remission revealed that persistent mutations in genes associated with clonal hematopoiesis did not have value for predicting relapse ...but that persistent mutations in other leukemia-associated genes had such value.
Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) were recently demonstrated in acute myeloid leukemia (AML), but their prevalence and prognostic impact remain to be explored in ...large extensively characterized AML series, and also in various other hematologic malignancies. Here, we demonstrate in 893 newly diagnosed cases of AML mutations in the IDH1 (6%) and IDH2 (11%) genes. Moreover, we identified IDH mutations in 2 JAK2 V617F myeloproliferative neoplasias (n = 96), a single case of acute lymphoblastic leukemia (n = 96), and none in chronic myeloid leukemias (n = 81). In AML, IDH1 and IDH2 mutations are more common among AML with normal karyotype and NPM1mutant genotypes. IDH1 mutation status is an unfavorable prognostic factor as regards survival in a composite genotypic subset lacking FLT3ITD and NPM1mutant. Thus, IDH1 and IDH2 mutations are common genetic aberrations in AML, and IDH1 mutations may carry prognostic value in distinct subtypes of AML.
To address the impact of cellular origin on acute myeloid leukemia (AML), we generated an inducible transgenic mouse model for MLL-AF9-driven leukemia. MLL-AF9 expression in long-term hematopoietic ...stem cells (LT-HSC) in vitro resulted in dispersed clonogenic growth and expression of genes involved in migration and invasion. In vivo, 20% LT-HSC-derived AML were particularly aggressive with extensive tissue infiltration, chemoresistance, and expressed genes related to epithelial-mesenchymal transition (EMT) in solid cancers. Knockdown of the EMT regulator ZEB1 significantly reduced leukemic blast invasion. By classifying mouse and human leukemias according to Evi1/EVI1 and Erg/ERG expression, reflecting aggressiveness and cell of origin, and performing comparative transcriptomics, we identified several EMT-related genes that were significantly associated with poor overall survival of AML patients.
•Generation of an inducible and reversible mouse model for MLL-AF9-driven AML•The cell of origin controls aggressiveness and outcome of MLL-AF9-mediated AML•The EMT transcription factor ZEB1 controls AML cell migration and invasion•Expression of multiple EMT-related genes is associated with poor outcome in human AML
Stavropoulou et al. show that MLL-AF9 expression in mouse long-term hematopoietic stem cells causes invasive, chemoresistant acute myeloid leukemia (AML) that expresses genes related to epithelial-mesenchymal transition (EMT). Expression of EMT-related genes in human AML is associated with poor patient survival.
High white blood cell count at presentation is an unfavorable prognostic factor for treatment outcome in intermediate cytogenetic risk acute myeloid leukemia. Since the impact of white blood cell ...count on outcome of subgroups defined by the molecular markers NPMc(+) and FLT3-internal tandem duplication (ITD) is unknown, we addressed this issue.
We studied the effect of white blood cell count on outcome in a clinically and molecularly well-defined cohort of 525 patients with acute myeloid leukemia using these molecular markers. In addition, since an increased white blood cell count has been associated with an increased FLT3-ITD/FLT3 (wild-type) ratio, we investigated whether the effect of white blood cell count on outcome could be explained by the FLT3-ITD/FLT3 ratio.
This analysis revealed that white blood cell count had no impact on outcome in patients with the genotypic combinations 'NPMc(+) without FLT3-ITD' and 'NPM1 wild-type with or without FLT3-ITD'. In contrast, white blood cell count had a significant impact on complete remission rate (P=0.034), event-free survival (P=0.009) and overall survival (P<0.001) in patients with the genotypic combination 'NPMc(+) with FLT3-ITD'. A FLT3-ITD/FLT3 ratio greater than 1 was also associated with a reduced complete remission rate (P=0.066) and significantly reduced event-free survival (P= 0.001) and overall survival (P=0.001) in patients with the genotypic combination 'NPMc(+) with FLT3-ITD'. Multivariable analysis revealed that white blood cell count and FLT3-ITD/FLT3 ratio were independent prognostic indicators for outcome in the subgroup with the genotypic combination 'NPMc(+) with FLT3-ITD'.
Our results demonstrate that both high white blood cell count and FLT3-ITD/FLT3 ratio are prognostic factors in patients with acute myeloid leukemia with the genotypic combination 'NPMc(+) with FLT3-ITD'.
Somatic mutations in the additional sex comb-like 1 (ASXL1) gene have been described in various types of myeloid malignancies, including acute myeloid leukemia. Analysis of novel markers, such as ...ASXL1 mutations, in independent clinical trials is indispensable before considering them for clinical decision-making. We analyzed 882 well-characterized acute myeloid leukemia cases to determine the prevalence and prognostic impact of ASXL1 exon12 mutations. Truncating ASXL1 mutations were present in 46 cases (5.3%). ASXL1 mutations were inversely associated with FLT3 internal tandem duplications and mutually exclusive with NPM1 mutations. ASXL1 mutations were an unfavorable prognostic factor as regards survival (median overall survival 15.9 months vs. 22.3 months; P=0.019), with a significantly lower complete response rate (61% vs. 79.6%; P=0.004). In multivariate analyses, ASXL1 mutations were independently associated with inferior poor overall survival (HR 1.52, P=0.032). In conclusion, ASXL1 mutations are common mutations in acute myeloid leukemia and indicate a poor therapy outcome.
Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual ...patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.
•Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival.•Mutant TP53 AML/MDS-EB should be considered a single molecular disease entity.
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This investigation of 285 cases of acute myelogenous leukemia combined sophisticated analyses of gene-expression profiles with cytogenetic findings, mutational status, and morphologic characteristics ...to identify distinct groups of patients. These groupings were related to the outcome of treatment.
Sophisticated analyses of gene-expression profiles with cytogenetic findings, mutational status, and morphologic characteristics.
Acute myeloid leukemia (AML) is not a single disease but a group of neoplasms with diverse genetic abnormalities and variable responses to treatment. Cytogenetics and molecular analyses can be used to identify subgroups of AML with different prognoses. For instance, the translocations inv(16), t(8;21), and t(15;17) herald a favorable prognosis, whereas other cytogenetic aberrations indicate poor-risk leukemia.
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Abnormalities involving 11q23, t(6;9), or 7(q) are defined as poor-risk markers by some groups
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and as intermediate-risk markers by others.
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These inconsistencies and the absence of cytogenetic abnormalities in a considerable proportion of patients argue for refinement of the classification . . .
1 Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
2 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA; The ...Broad Institute of M.I.T. and Harvard, Cambridge, USA
3 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
Correspondence: Peter J.M. Valk, Erasmus University Medical Center Rotterdam, Department of Hematology, Ee1391a, Dr. Molewaterplein 50, 3015 GE Rotterdam Z-H, The Netherlands. E-mail: p.valk{at}erasmusmc.nl
We examined the gene expression profiles of two independent cohorts of patients with acute myeloid leukemia n=247 and n=214 (younger than or equal to 60 years) to study the applicability of gene expression profiling as a single assay in prediction of acute myeloid leukemia-specific molecular subtypes. The favorable cytogenetic acute myeloid leukemia subtypes, i.e., acute myeloid leukemia with t(8;21), t(15;17) or inv(16), were predicted with maximum accuracy (positive and negative predictive value: 100%). Mutations in NPM1 and CEBPA were predicted less accurately (positive predictive value: 66% and 100%, and negative predictive value: 99% and 97% respectively). Various other characteristic molecular acute myeloid leukemia subtypes, i.e., mutant FLT3 and RAS , abnormalities involving 11q23, –5/5q-, –7/7q-, abnormalities involving 3q (abn3q) and t(9;22), could not be correctly predicted using gene expression profiling. In conclusion, gene expression profiling allows accurate prediction of certain acute myeloid leukemia subtypes, e.g. those characterized by expression of chimeric transcription factors. However, detection of mutations affecting signaling molecules and numerical abnormalities still requires alternative molecular methods.
Key words: acute myeloid leukemia, gene expression profiling, prediction.
We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients ...with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with
CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with
NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates).
► Specific and distinct DNA methylation patterns characterize distinct forms of AML ► DNA methylation profiling identified 5 novel clinically relevant subtypes of AML ► A 15-gene DNA methylation classifier predicted clinical outcome of AML patients ► A set of 45 genes was consistently aberrantly methylated across all AML subtypes.