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  • 1
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    Prognostic Significance of DNA Methyltransferase 3A Mutations in Cytogenetically Normal Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2506-2506
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2506-2506
    Abstract: Abstract 2506 Introduction: The development of massively parallel sequencing technologies has led to the identification of somatic DNA methyltransferase 3A (DNMT3A) gene mutations in acute myeloid leukemia (AML), with the highest frequency being found in cytogenetically normal (CN) AML. DNMT3A mutations have been suggested to predict poor clinical outcome in AML, but only few data are available on their prognostic significance within CN-AML. The aim of this study was to determine the frequency, the main associated features, and the prognostic significance of DNMT3A mutations in CN-AML. Patients and methods: This retrospective study was performed in 123 young adult patients (16–60 years) with previously untreated primary CN-AML and enrolled on two concomitant protocols of the Acute French Leukemia Association (ALFA), the ALFA-9801 and ALFA-9802 trials. DNMT3A mutations were screened on genomic DNA by PCR and direct Sanger sequencing. We focused our screening on the 3 conserved domains of DNMT3A (the proline-tryptophane-tryptophane-proline (PWWP) domain, the ADD-type zinc finger domain, and the C5-methyltransferase domain), corresponding to exons 8–9 and 11–23. The patients were also assessed for the presence of FLT3 internal tandem duplication (FLT3-ITD), FLT3 tyrosine kinase domain (FLT3-TKD), NPM1, CEBPA, WT1, IDH1, and IDH2 mutations. Results: Thirty-eight DNMT3A mutations were identified in 36 of the 123 (29%) patients. These alterations consisted of 36 nucleotide substitutions and 2 frameshift deletions. Thirty out of 36 (83%) nucleotide substitutions affected the amino acid residue R882 (R882H, n = 21; R882C, n = 7; R882P, n = 2), 5 represented other missense alterations, and 1 was a nonsense mutation. Two patients exhibited 2 heterozygous missense mutations in different exons, and one patient had a homozygous missense mutation. DNMT3A mutated and wild-type cases did not differ in terms of age, gender, and white blood cell (WBC) count at presentation. DNMT3A mutations were strongly associated with the French-American-British (FAB) subtypes M4/M5 (P =.0002) and the presence of NPM1 mutations (P =.0006), and tended to often co-occur with IDH1R132 mutations (P = .09). In the entire cohort, complete remission rate was found lower in DNMT3A mutated patients than in DNMT3A wild-type patients, but without reaching statistical significance (80% vs 90%, P =.24). DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P =.02) and overall survival (5-year OS: 23% vs 45%, P =.02) compared to DNMT3A wild-type patients. We next performed subgroup analysis according to the NPM1/FLT3-ITD genotypes. In patients with the non-favorable genotypes, that is NPM1 mutated/FLT3-ITD positive, NPM1 wild-type/FLT3-ITD positive, NPM1 wild-type/FLT3-ITD negative (n = 86), 18 (21%) had a concomitant DNMT3A mutation. In this high-risk subgroup of CN-AML, DNMT3A mutations conferred a worse clinical outcome (5-year EFS: 0% vs 23%, P =.02; 5-year OS: 14% vs 37%, P =.06). In patients with the favorable genotype NPM1 mutated/FLT3-ITD negative (n = 37), 18 (49%) were found to display a concomitant DNMT3A mutation. Within this favorable subgroup, patients carrying a DNMT3A mutation had a significantly inferior EFS and OS compared to DNMT3A wild-type patients (5-year EFS: 25% vs 65%, P =.01; 5-year OS: 29% vs 76%, P =.02). Furthermore, in multivariate analysis including age, WBC count, NPM1/FLT3-ITD genotypes, and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS (hazard ratio = 2.29; 95% CI, 1.42 to 3.70; P =.0007) and OS (hazard ratio = 2.34; 95% CI, 1.37 to 4.00; P =.002). Conclusion: DNMT3A mutations are one of the most common gene mutations in CN-AML and independently predict poor clinical outcome. Testing for DNMT3A mutations could help further improve risk stratification in CN-AML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2506.2506
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 2
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    New-generation sequencing (NGS) in hematologic oncology laboratories
    John Libbey Eurotext ; 2013
    In:  Hématologie Vol. 19, No. 2 ( 2013-03), p. 112-122
    Details
    In: Hématologie, John Libbey Eurotext, Vol. 19, No. 2 ( 2013-03), p. 112-122
    Type of Medium: Online Resource
    ISSN: 1264-7527 , 1950-6368
    URL: Article
    DOI: 10.1684/hma.2013.0792
    Language: French
    Publisher: John Libbey Eurotext
    Publication Date: 2013
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  • 3
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    Deletion of the Tumor Suppressor Gene NF1 Is Found In 3.5% of 485 De Novo Adult Myeloid Leukemia and Is Correlated with Unfavourable Cytogenetic: On Behalf of the ALFA Group
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4171-4171
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4171-4171
    Abstract: Abstract 4171 NF1 acts as a tumor-suppressor gene by encoding neurofibromin1, a GTPase-activating protein (GAP) inhibiting Ras signaling pathway. Germline mutations or microdeletions of NF1 are responsible for neurofibromatosis type 1, and the somatic loss of the remained wild-type allele lead to malignant tumors or juvenile myelomonocytic leukemia (JMML). Furthermore, several studies revealed heterozygous somatic deletions of the 17q11.2 region including NF1 in adult myeloid malignancies. The reported frequencies of this abnormality varied between 2.6% and 11% in AML and this variation can be attributable to heterogeneity or size of the analysed cohorts. Previously, we analyzed 131 de novo AML cases (AML3 excluded) by Agilent™ 105K microarrays. 6/131 cases (4.6%) showed somatic deletions in 17q11.2, including a small minimal deleted region of 300 kb comprising the entire NF1 gene. To further investigate the incidence of NF1 deletion in de novo AML, 354 additional patients were therefore screened for the deletion by quantitative real-time PCR (Primers and TaqMan-based probe Hs 01778367_cn from Applied Biosystems), and FISH (NF1/MPO probe KBI-40144 from Kreatech) was performed to confirm the loss of NF1 copy number. Altogether, heterozygous NF1 deletion was observed in 17/485 (3.5%) de novo AML. Clinico-biological data were available from 14 NF1 deleted patients and 380 non-deleted patients included in the ALFA-9801 and 9802 French Trials. There were no significant differences between the 2 groups in age, sex ratio, leukocytosis, FAB classification of AML, mutational status of FLT3, NPM1, CEBPα and IDH. Interestingly, NF1 deletion was significantly correlated with unfavourable cytogenetic (50% vs 18%, p=0.008) and especially with monosomal karyotype (29% vs 9%, p=0.03). However, no statistical significant differences were observed for complete remission rate, relapse risk 3 years after diagnosis and 3-years overall survival. Screening for bi-allelic inactivation by sequencing the remained allele in NF1 deleted patients is in progress. We next evaluated NF1 gene expression for 93 patients of our cohort (3 with NF1 deletion and 90 without) by Affymetrix U133 Plus 2.0 microarrays. The 3 NF1 deleted patients revealed a significant reduced mean of NF1 expression level. Interestingly, about 10% of the NF1 non-deleted patients presented a similar decrease in NF1 expression rate. This suggests that mechanisms for transcriptional regulation (such as mutations or epigenetic silencing of NF1) may also contribute to AML pathogenesis. In conclusion, NF1 deletions occur in only 3.5% of de novo AML and are associated with unfavourable cytogenetic. This relatively low frequency of NF1 deletion can however be counterbalanced by others alterations acting at the transcriptional level and this remains to be investigated. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.4171.4171
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 4
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    Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group
    Ferrata Storti Foundation (Haematologica) ; 2018
    In:  Haematologica Vol. 103, No. 5 ( 2018-05), p. 822-829
    Details
    In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 103, No. 5 ( 2018-05), p. 822-829
    Type of Medium: Online Resource
    ISSN: 0390-6078 , 1592-8721
    URL: Article
    DOI: 10.3324/haematol.2017.183525
    Language: English
    Publisher: Ferrata Storti Foundation (Haematologica)
    Publication Date: 2018
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  • 5
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    Mutations of TET2, IDH1, IDH2 and ASXL1 In Chronic Myeloid Leukemia.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3377-3377
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3377-3377
    Abstract: Abstract 3377 It is generally accepted that the BCR-ABL oncoprotein transformes haematopoietic stem cell and initiates chronic myeloid leukemia (CML). However, leukemogenesis is a complex process, and genomic heterogeneity of the chronic phase (CP) of the disease has been reported. At the molecular level, this intrinsic heterogeneity could support a causative link with the varying response to treatment and disease progression. Genetic analysis of candidate genes in myeloid malignancies reported mutations of the ten-eleven translocation 2 (TET2), the isocitrate deshydrogenase (IDH) 1 and IDH2, and the additional sex combs like 1 (ASXL1) genes in myeloproliferative, acute myeloid and myelodysplasic neoplasms. Similarly, we can stipulate that these candidate genes may contribute to phenotypic heterogeneity of CML. To investigate whether TET2, IDH1, IDH2 and ASXL1 defect could represent a significant event in CML, we selected 91 CML patients (pts) treated with imatinib (IM) at first line and presenting five profiles of IM response at time of the analysis: 1) 25 pts in major molecular response (MMR) at 12 months of IM; 2) 11 pts in CCR but presenting additional Philadelphia (Ph) negative clonal evolution; 3) 20 pts in partial cytogenetic response at 18 months of IM, referred as primary resistant (R1); 4) 20 pts in acute transformation 4 to 72 months after onset IM; and 5) 15 pts relapsing in CP of the disease, referred as secondary resistant (R2). The search for mutation was performed by sequencing the entire TET2 coding region (11 exons), the IDH1 and IDH2 exon 4 and the ASXL1 exon 12. Analysis of paired samples from CML diagnosis, time of IM response and, when available, CCR revealed: 1) 2 pts (2.2%) in acute transformation presenting 3 TET2 stop mutations not located within conserved region (del at A2079, substitution T4893A - both also been detected at diagnosis -, and del at C4851 which has not been detected at diagnosis, even by mutation-specific ASO-PCR); 2) no IDH1 and IDH2 mutation; and 3) 8 pts (8.7%) presenting ASXl1 stop mutations at diagnosis. Among them, 3 pts (two ins at G646 and one ins at V751) have reached MMR without detected mutations at this time; one R1 pt presenting ins at G646 had major cytogenetic response with 5% Ph+ cells but the mutation was not found at this time and the pt have progressed to MMR 9 months later; one pt with 23 bp del at R634 has evolved in acute transformation with detected mutation at this time; and 3 R2 pts presenting either 4 bp del at S895, del at R860 or 2 pb ins at A752 have lost CCR associated with lost of hematologic response in one case. In this later group of 3 pts, except for del at R860, all ASXL1 mutations were found in samples at time of relapse. We therefore conclude that, contrary to what has been reported in other myeloid malignancies, TET2, IDH1 and IDH2 are not commonly acquired in CML and may not represent a major genetic event in CML transformation. However, ASXL1 alteration seems to be an early event in CML leukemogenesis but does not seem to participate in the disease transformation. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3377.3377
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
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    Minimal Residual Disease Monitoring In t(8;21) Acute Myeloid Leukemia Based On RUNX1-RUNX1T1 Fusion Quantification On Genomic DNA
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 1353-1353
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1353-1353
    Abstract: Acute myeloid leukemia (AML) with t(8;21) chromosomal translocation, leading to the RUNX1-RUNX1T1 fusion, belong to the favorable risk AML subset. However, relapse incidence may reach 30-40% in these patients. Minimal residual disease monitoring (MRD) based on the quantification of RUNX1-RUNX1T1 fusion transcript by real-time quantitative PCR (RQ-PCR) has been reported to be an independent prognostic factor for the risk of relapse. The specificity of the RUNX1-RUNX1T1 fusion and the high sensitivity of RQ-PCR techniques have made RUNX1-RUNX1T1 an ideal marker to assess treatment response in t(8;21) AML. Undetectable MRD could mean either that tumor cells persist in a latent state without RNA expression or that MRD level is below the sensitivity threshold. Studies in chronic myeloid leukemia showed that BCR-ABL DNA was still detectable in patients in long-term complete molecular response with undetectable BCR-ABL fusion transcript. Using a similar approach, we investigated the use of RUNX1-RUNX1T1 DNA as a MRD marker in t(8;21) AML, instead of RUNX1-RUNX1T1 mRNA. This approach allows linking results directly to the amount of leukemic cells, since each leukemic cell contains one copy of the RUNX1-RUNX1T1 sequence, while the level of RUNX1-RUNX1T1 mRNA may vary from a patient to another. Methods This study focuses on 17 patients with t(8;21) AML included in the CBF-2006 trial and for whom frozen material was available for further molecular analysis. Bone marrow and blood samples were collected at AML diagnosis and during follow-up, as defined in the CBF-2006 trial. Eight patients relapsed during follow-up and 9 were still in complete remission at the end of the study. Interestingly, 3 patients relapsed with a previously undetectable MRD (in blood and bone marrow samples). First, we identified the breakpoints in the RUNX1 and RUNX1T1 genes for each patient using long-range PCR approaches, coupled with next-generation sequencing (NGS) on Personal Genome Machine™ (PGM). The stability of the RUNX1-RUNX1T1 rearrangement at relapse was checked by Sanger sequencing. Then, we performed quantification of RUNX1-RUNX1T1 DNA by RQ-PCR using Taqman technology. For each patient, a primer pair and a probe were designed using the patient's unique RUNX1-RUNX1T1 breakpoint sequence. The forward and reverse primers were located in RUNX1 and RUNX1T1 genes, respectively, and the probe was located at the RUNX1-RUNX1T1 junction. Calibration curves were established using 10-fold dilutions of the diagnostic DNA of each patient in normal control DNA. Results were given as a ratio of chimeric DNA amount in the follow-up sample to chimeric DNA amount at diagnosis. Results Chromosomal breakpoints were located in RUNX1 intron 5 for all patients. RUNX1T1 breakpoints were located in intron 1b for 15 patients, and in intron 1a for 2 patients (Fig. 1). Quantification failed for 1 patient which was further leave up. Between 2 and 7 follow-up samples were studied for the other patients (median 4.5). DNA monitoring was strongly correlated with RNA monitoring (Fig. 2). Sensitivity threshold, determined by the lowest diagnostic sample dilution which gives a signal, was 10-5 for 7 patients, 10-4 for 6 patients, and only 5.10-4 for 3 patients. MRD was detectable in 31 samples and undetectable in 30 samples by both methods, whereas MRD was detectable only on RNA in 7 samples, probably because of a lack of sensitivity of the RQ-PCR assay. Interestingly, RUNX1T1-RUNX1 DNA was detected in 3 samples from 2 patients who relapsed and for whom RUNX1T1-RUNX1 transcript was undetectable, despite a good RNA quality. Conclusions Overall, RUNX1-RUNX1T1 MRD levels on DNA and RNA were quite similar. The level of mRNA expression did not seem to change during follow-up when compared with the amount of DNA. MRD monitoring on genomic DNA is a useful method, but with sensitivity variations depending on the patient's breakpoint sequence and the efficiency of the RQ-PCR assay. DNA has potential advantages: it is more stable than RNA and a best substrate for collection, processing, transport and storage. Additionally, interpretation of the results is easier because it is closely related to the number of leukemic cells. However, this method greatly increases complexity, time of implementation, and cost of monitoring MRD, which limits its interest in routine practice. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.1353.1353
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 7
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    Germline PAX5 mutation predisposes to familial B-cell precursor acute lymphoblastic leukemia
    American Society of Hematology ; 2021
    In:  Blood Vol. 137, No. 10 ( 2021-03-11), p. 1424-1428
    Details
    In: Blood, American Society of Hematology, Vol. 137, No. 10 ( 2021-03-11), p. 1424-1428
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2020005756
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 8
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    Prognostic Impact of Wilms Tumor 1 Single Nucleotide Polymorphism rs16754 In Older Patients with Acute Myeloid Leukemia
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2701-2701
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2701-2701
    Abstract: Abstract 2701 The Wilms tumor 1 (WT1) gene, located at chromosome band 11p13, encodes a transcriptional regulator involved in normal hematopoietic development. The role of WT1 in acute myeloid leukemia (AML) has been underlined by the finding of WT1 overexpression in most AML cases and WT1 gene mutations in approximately 10% of AML patients. Recently, the minor allele of the silent Arg301 single nucleotide polymorphism (SNP) (rs16754), which is a 903A 〉 G substitution in WT1 exon 7, was suggested to predict a favorable prognosis in adult patients with cytogenetically normal (CN) acute myeloid leukemia (AML). In contrast, no prognostic impact of this SNP was found in another study performed in pediatric AML. Our aim was to evaluate the frequency, the main associated features and the prognostic significance of WT1 SNP rs16754 in elderly patients with AML. Diagnostic bone marrow or peripheral blood samples were analyzed from 266 patients (age 50 to 70 years) with previously untreated de novo AML included in the French ALFA-9801 trial. WT1 SNP rs16754 and gene mutations of NPM1, CEBPA, FLT3 (internal tandem duplication, ITD), WT1 (exon 7 and 9), IDH1 and IDH2 (exon 4) were screened on genomic DNA by direct sequencing and fragment-length analysis for the detection of small insertion/deletion. The minor allele of WT1 SNP rs16754 was found in 85 (32%) out of 266 cases. Patients heterozygous or homozygous for minor allele (WT1AG or WT1GG) and patients homozygous for the major allele (WT1AA) did not significantly differ in terms of age, gender, white blood cell (WBC) count, FAB subtypes, cytogenetic categories, and gene mutations when those mutations are considered separately. However, among CN-AML, the frequency of the favorable genotype defined by the presence of NPM1 mutation or CEBPA mutation without neither FLT3-ITD nor IDH1 mutation was significantly lower in patients with at least one minor allele than in patients with two major alleles (5% vs 23% of CN-AML, p=0.02). In univariate analysis, complete remission rate was found similar between patients with at least one minor allele and patients with two major alleles (76% vs 75%, p=0.88). Patients with at least one minor allele tended to have a shorter median delay to relapse (7 vs 12.2 months, p=0.06) and had a significantly shorter overall survival compared to patients with the two major alleles (5-year OS, 14% vs 26%, p=0.02). In the subset of CN-AML (n=113), the presence of at least one minor allele was also associated with a shorter median delay to relapse (6.9 vs 12.5 months, p=0.02) but only a trend regarding overall survival was observed (5-year OS, 17% vs 30%, p=0.1). In multivariate analysis considering age, WBC count, cytogenetics (favorable, intermediate and unfavorable categories) as covariates, WT1 SNP rs16754 status was found to be an independent prognostic factor for relapse risk (HR 1.56, 95% CI 1.06 to 2.30, p=0.03) and overall survival (HR 1.54, 95% CI 1.08 to 2.20, p=0.02). Thus, in our cohort of older AML patients, the minor allele of WT1 SNP rs16754 appears to confer a relatively poor prognosis, which is in contradiction to what has been reported so far. Overall, our data suggest that WT1 SNP rs16754 is an interesting marker that may contribute to refine prognosis in AML, at least in this age group of patients. Further investigations are needed to clarify the relationship between WT1 SNP rs16754 and treatment outcome in AML and elucidate the biological effects of this SNP. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2701.2701
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 9
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    Prognostic Analysis of GATA2 Mutations in CEBPA-Mutated Acute Myeloid Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2360-2360
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2360-2360
    Abstract: Background CEBPA mutations are found in approximately 10% of acute myeloid leukemia (AML). Recent studies revealed an association between CEBPA and GATA2 mutations. GATA2 gene encodes a transcription factor involved in hematopoiesis. In two recent studies (Grossmann et al., BJH 2013; Fasan et al., Leukemia 2013), GATA2 mutations appeared to be associated specifically with double CEBPA mutations and improved overall survival (OS). In contrast, another study failed to show any impact on OS (Green et al., BJH 2013). The aim of our study was to investigate the prognostic significance of GATA2 mutations in a large cohort of patients with CEBPA-mutated AML. Patients and methods We studied a cohort of 128 patients with CEBPA-mutated AML treated with intensive chemotherapy. The entire coding region of CEBPA, NPM1 exon 12, and GATA2 exons 4 to 6 (that encode the two multifunctional zinc finger domains of the protein) were screened on genomic DNA by PCR and direct Sanger sequencing. FLT3 internal tandem duplications (FLT3-ITD) were screened on genomic DNA by PCR and fragment analysis. Additionally, transcriptome analysis was performed with Affymetrix HG U133 Plus 2.0 array in pre-treatment samples from 72 patients for which RNA was available. Results Median age at AML diagnosis in the whole cohort was 50 years (range, 3-80). Almost all patients belonged to the intermediate cytogenetic risk-group (n=117), of which 90 had a normal karyotype. The remaining patients had favorable (n=1) or adverse cytogenetics (n=4). CEBPA mutations were distributed as follows: 29 single-mutated (sm) cases with N-terminal (N-ter) mutations, 12 sm cases with C-terminal (C-ter) mutations, 80 double-mutated (dm) cases with both N-ter and C-ter mutations, 2 cases with homozygous N-ter and 5 cases with homozygous C-ter mutations. GATA2 mutations were found in 29/128 patients (23%) and were significantly associated with CEBPA dm cases (4/41 sm vs 25/87 dm: Fisher's exact test p=0.022). NPM1 mutations were detected in 12 patients. They were specifically associated with CEBPA sm cases (12/40 sm vs 0/78 dm, p 〈 0.001) and mutually exclusive with GATA2 mutations (12/93 GATA2 wild-type vs 0/25 GATA2 mutated cases, p 〈 0.001). In contrast with previous studies, FLT3-ITD and GATA2 mutations did co-occur in our cohort, with 3 GATA2 mutants identified in 10 FLT3-ITD positive patients. Transcriptome analysis revealed that GATA2 mutations were not associated with a specific gene expression signature. As previously described, we found that CEBPA dm AML harbored a specific gene expression profile distinct from CEBPA sm cases. Since AML with homozygous CEBPA mutations were found to have a similar gene expression signature as CEBPA dm AML, we decided to pool them together for prognostic analysis. Overall, complete remission was achieved in 113 patients (88%), of whom 36 relapsed (estimated cumulated incidence of relapse [CIR] at 3 and 5 years, 39%). Neither age nor karyotype or gene mutations (including NPM1, FLT3, GATA2 and type of CEBPA mutation) significantly influenced CIR in multivariate analysis. Five-year OS was estimated at 58% in the whole cohort, with longer OS in cases with normal karyotype (p=0.05) and double CEBPAmutations (sm vs dm, p=0.03). In multivariate analysis, younger age (p=0.020) and normal karyotype (p=0.029) remained the only factors significantly associated with a longer OS. Conclusions This study confirmed the strong association between GATA2 mutations and CEBPA double mutations, in line with previous studies. However, we did not find any prognostic impact of GATA2 mutations in our cohort of CEBPA-mutated AML. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2360.2360
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 10
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    A novel type of NPM1 mutation characterized by multiple internal tandem repeats in a case of cytogenetically normal acute myeloid leukemia
    Ferrata Storti Foundation (Haematologica) ; 2018
    In:  Haematologica Vol. 103, No. 12 ( 2018-12), p. e575-e577
    Details
    In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 103, No. 12 ( 2018-12), p. e575-e577
    Type of Medium: Online Resource
    ISSN: 0390-6078 , 1592-8721
    URL: Article
    DOI: 10.3324/haematol.2018.190959
    Language: English
    Publisher: Ferrata Storti Foundation (Haematologica)
    Publication Date: 2018
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