Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia

Boultwood, Jacqueline; Perry, Janet; Pellagatti, Andrea; Fernández-Mercado, Marta; Fernandez-Santamaria, C; Calasanz, Marı́a José; Larráyoz, María José; García‐Delgado, M.; Giagounidis, Aristoteles; Malcovati, Luca; Porta, Matteo Giovanni Della; Jädersten, Martin; Killick, Sally; Hellström‐Lindberg, Eva; Cazzola, Mario; Wainscoat, James S.

doi:10.1038/leu.2010.20

Cited by 237 publications

(198 citation statements)

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“…In line with previous studies in AML, [6][7][8][9]11,27,28 we found that c.1934dupG (p.G646WfsX12) was the most frequent ASXL1 mutation, accounting for 60% of the ASXL1 mutated cases. In a prior, large study of 501 patients with unselected AML, Chou et al found ASXL1 mutations in 10.8% of the patients.…”

Section: Discussionsupporting

confidence: 79%

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ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group

et al. 2015

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ABSTRACTand clinical impact of these mutations in the context of other clinical and genetic factors in a well-defined population of patients intensively treated in trials of the GermanAustrian AML Study Group (AMLSG). Methods PatientsA total of 1696 younger AML patients (18 to 61 years) were studied. Patients were enrolled in prospective treatment protocols of the AMLSG), namely AML HD98A 12 (n=733; NCT00146120), AMLSG 07-04 13 (n=893; NCT00151242), and APL HD95 14 (n=70) for the patients with acute promyelocytic leukemia (APL). The clinical studies were approved by the local ethics review committees and all patients gave informed consent for both treatment and cryopreservation of leukemia samples according to the Declaration of Helsinki. The only criterion to include patients in our study was the availability of a pretreatment bone marrow or peripheral blood specimen for analysis of ASXL1 mutations. Cytogenetic and additional molecular analyses were performed as previously described. 15-19 ASXL1 mutation analysisA detailed description of the ASXL1 mutation analysis is provided in the Online Supplementary Material. Briefly, genomic DNA was used as a template for polymerase chain reactions to amplify several fluorescently-labeled DNA fragments covering the entire exon 12 (AMLSG 07-04) or regions within exon 12 (AML HD98A and APL HD95) identified as main mutation clusters in AML. 6,20 Amplicons were screened for mutations by a GeneScan-based fragment analysis (Online Supplementary Figures S1 and S2). Samples classified as mutated after the GeneScan analysis (Online Supplementary Figure S2) were further analyzed by direct sequencing to validate the mutation and to determine the mutation type. Statistical analysisStatistical analyses of clinical outcome were performed according to previous reports. 16 The median follow-up for survival was calculated according to the method of Korn. 21 The definition of complete remission (CR), event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS) as well as cytogenetic categorization into favorable-, intermediate-, and adverse-risk groups followed recommended criteria. 22 Pairwise comparisons between patients' characteristics (covariates) were performed using the Mann-Whitney test for continuous variables and the Fisher exact test for categorical variables. The Kaplan-Meier method was used to estimate the distribution of EFS, RFS and OS. 23 Estimation of confidence intervals for the survival curves was based on the Greenwood formula for standard error estimation. A logistic regression model was used to analyze associations between baseline characteristics and the achievement of CR. A Cox model was used to identify prognostic variables. 24 In addition to ASXL1 mutation status, age, sex, hemoglobin level, logarithm of white blood cell count, type of AML (de novo, secondary AML, therapy-related AML), percentage of peripheral blood and bone marrow blasts, cytogenetic risk group, 22 and mutational status of NPM1, FLT3 (ITD and TKD),), RUNX1, MLL (PTD), and DN...

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Section: Discussionsupporting

confidence: 79%

“…Of note, the majority (>90%) of the mutations clustered within or around a glycine-rich domain located between amino acids 642 and 685. 27 …”

Section: Frequency and Types Of Asxl1 Mutationsmentioning

confidence: 99%

ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group

et al. 2015

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“…Interstitial deletion of the long arm of chromosome 5 (del(5q)), is the most common karyotypic abnormality in myeloid neoplasms, observed in 10-15% of patients with myelodysplastic syndromes (MDS) [1][2][3][4][5] or primary acute myeloid leukemia (pAML) [6,7], and in up to 40% of secondary myeloid leukemias (sAML) [8]. While a smaller fraction of more homogenous patients with the isolated del(5q) and classical 5q-syndrome show more favorable prognosis [9,10], the majority of myeloid neoplasms with del(5q) are morphologically heterogeneous, and have additional cytogenetic abnormalities [7,11,12].…”

Section: Introductionmentioning

confidence: 99%

Recurrent genetic defects on chromosome 7q in myeloid neoplasms

et al. 2014

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“…39 The frequency of mutations of ASXL-1 is approximately 10% in MDS and higher in CMML. 40,41 Mutations in TET-2 in myeloid disorders have been reported by several groups. [42][43][44][45] Nonsense mutations of TET2 have been reported in 26% of patients with MDS.…”

Section: Molecular Alterations With Prognostic Value In Mds: Not Onlymentioning

confidence: 99%

Prognosis of Myelodysplastic Syndromes

Garcia-Manero

2010

Hematology

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The myelodysplastic syndromes (MDS) are a very complex group of hematopoietic disorders. The degree of complexity relates not only to the intrinsic pathobiological characteristics of the disease, but also to the group of patients whom it affects most frequently: older individuals or those who have been exposed to prior forms of chemotherapy. It is therefore crucial to develop clinical tools to predict with a certain degree of precision the prognosis and outcome for patients with specific subtypes of MDS in specific clinical situations. At the present time, patients with MDS are diagnosed using a set of well-established histopathological criteria. Prognosis is established using classifications that include morphological features, percentage of blasts, and clinical and molecular characteristics such as peripheral cytopenias and cytogenetics. The International Prognostic Scoring System (IPSS) is a classic example of this type of classification. Over the last 5 years, there has been an intense effort to develop new prognostic systems for MDS, and new molecular alterations with potential prognostic value have been discovered. Over the same period of time, several new therapeutic interventions have been developed for patients with MDS. Biomarkers of response to these agents, in particular for the hypomethylating agents, are needed to predict clinical benefit. This review summarizes current prognostic models of MDS and new molecular alterations with potential prognostic potential.

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Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia

Abstract: et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia.

Cited by 237 publications

References 9 publications

ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group

ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group

Recurrent genetic defects on chromosome 7q in myeloid neoplasms

Prognosis of Myelodysplastic Syndromes

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