Prognostic Significance of DNA Methyltransferase 3A Mutations in Cytogenetically Normal Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2506-2506
Author(s):  
Aline Renneville ◽  
Nicolas Boissel ◽  
Olivier Nibourel ◽  
Céline Berthon ◽  
Nathalie Helevaut ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Wild Type ◽  
Poor Clinical Outcome ◽  
Nucleotide Substitutions ◽  
Dna Methyltransferase 3A ◽  
Wbc Count

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.

INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia

Leukemia ◽  
2015 ◽  
Vol 29 (7) ◽  
pp. 1485-1495 ◽  
Author(s):  
I Dzneladze ◽  
R He ◽  
J F Woolley ◽  
M H Son ◽  
M H Sharobim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Therapy Resistance ◽  
Poor Clinical Outcome ◽  
Acute Myeloid

scholarly journals A Computational Based Approach for Identification and Validation of Gene Mutations As Surrogate Markers of Gene Essentiality in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1414-1414
Author(s):  
Fernando Carazo ◽  
Edurne San Jose ◽  
Leire Garate ◽  
Estibaliz Miranda ◽  
Ana Alfonso Pierola ◽  
...  
Keyword(s):  
Cell Lines ◽  
Targeted Therapies ◽  
Myeloid Leukemia ◽  
Prior Information ◽  
Essential Gene ◽  
Gene Mutations ◽  
Surrogate Markers ◽  
Wild Type ◽  
Gene Essentiality ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic neoplasm characterized by a remarkable phenotypic and genomic heterogeneity. The recent characterization of genomic subtypes of AML based on large sequencing studies has provided the rationale for the development of targeted therapies based on the presence of specific genomic abnormalities. However, long term survival particularly in older patients remains a unmet medicalneed. Additionally, recent studies using RNA interference (RNAi) libraries have determined the existence of genes that are essential for the survival of multiple cancer cells. Understanding the effect of genomic alterations (mutations, deletions, translocations) on gene essentiality could favor the development of targeted therapies for specific subgroups of AML patients. However, current statistical methods such as the Benjamini-Hochberg (BH) procedure have shown limitations for controlling the false discovery rate (FDR) and have suboptimal sensitivity (recall of true positives) because the P-value correction does not include any prior information of individual tests. For this reason, in this study we developed a new large-scale statistical algorithm, which combine the RNAi libraries (more than 17.000 genes) data with mutational profiles, to identify gene essentialities associated with specific genomic mutations in order to explore this approach in AML. We adapted the Independent Hypothesis Weighting (IHW) procedure to the problem of identifying mutations as surrogate markers of gene essentiality, by using the gene mutation state in each cell line as prior information of a IHW problem. This approach was tested in 19 tumor subtypes, of the Cancer Cell Line Encyclopedia (CCLE) showing that it recalls new discoveries that cannot be identified with standard procedures in 17 out of 19 tumors, including the identification of up to 1,000 discoveries in tumor types in which BH recalls no discovery. These results demonstrated the accuracy of the IHW-based approach to identify gene mutations as surrogate markers of gene essentiality in the future. Once validated, we applied this computational model to the15 AMLcell lines of CCLE. The number of discoveries with an FDR of 20% increases from 2 (using the traditional BH correction), to 38 using our procedure, showing NRAS as the top mutation biomarker in the ranking. Interestingly, the algorithm identified one essential gene (NRAS) for NRAS mutated (NRAS-mut) and another essential gene (PTPN11) for NRAS wild type (NRAS-wt) AML cells, covering all samples of AMLs. To validate this hypothesis, we examined the effect of two different specific siRNAs for each gene (siPTPN11 and siNRAS) on cell proliferation of four AML cell lines: two lines with NRAS-mut (HL-60 and OCIAML3) and two with NRAS-wt (MV4-11 and HEL). Downregulation of NRAS expression significantly decreases the cell proliferation only in the 2 NRAS-mutated AML cell lines. Whereas the inhibition of PTPN11expression produced an equivalent effect, but specifically in the 2 NRAS-wt AML cell lines (Figure 1). These results confirmed our predictions and showed the essential role of NRAS or PTNPN11 in AML cell lines either with NRAS mutated or wild type, respectively. These results demonstrate that the application of our algorithm in the context of specific gene mutation not only may allow identification of directed therapies based on the mutation but can also define new gene essentialities amenable for targeted therapies providing new therapeutic strategies in patients with AML and potentially in other tumors. Disclosures Paiva: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.

Analysis of DNA methyltransferase 3A gene mutations in patients with Philadelphia-negative myeloproliferative neoplasms

2017 ◽  
Vol 6 (1) ◽  
pp. 81
Author(s):  
Najmaldin Saki ◽  
Neda Ketabchi ◽  
Mostafa Paridar ◽  
Javad Mohammadi-Asl ◽  
Alireza Abooali ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Myeloproliferative Neoplasms ◽  
Gene Mutations ◽  
Dna Methyltransferase 3A

Acute Myeloid Leukemia With Biallelic CEBPA Gene Mutations and Normal Karyotype Represents a Distinct Genetic Entity Associated With a Favorable Clinical Outcome

2010 ◽  
Vol 28 (4) ◽  
pp. 570-577 ◽  
Author(s):  
Annika Dufour ◽  
Friederike Schneider ◽  
Klaus H. Metzeler ◽  
Eva Hoster ◽  
Stephanie Schneider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Mutations ◽  
Gene Expression Profiles ◽  
Similar Frequency ◽  
Favorable Clinical Outcome ◽  
Acute Myeloid

Purpose CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal (CN) acute myeloid leukemia (AML). Patients and Methods Four hundred sixty-seven homogeneously treated patients with CN-AML were subdivided into moCEBPA, biCEBPA, and wild-type (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3, and MLL genes. Furthermore, we obtained gene expression profiles using oligonucleotide microarrays. Results Only patients with biCEBPA had an improved median overall survival when compared with patients with wtCEBPA (not reached v 20.4 months, respectively; P = .018), whereas patients with moCEBPA (20.9 months) and wtCEBPA had a similar outcome (P = .506). Multivariable analysis confirmed biCEBPA, but not moCEBPA, mutations as an independent favorable prognostic factor. Interestingly, biCEBPA mutations, compared with wtCEBPA, were never associated with mutated NPM1 (0% v 43%, respectively; P < .001) and rarely associated with FLT3 internal tandem duplication (ITD; 5% v 23%, respectively; P = .059), whereas patients with moCEBPA had a similar frequency of mutated NPM1 and a significantly higher association with FLT3-ITD compared with patients with wtCEBPA (44% v 23%, respectively; P = .037). Furthermore, patients with biCEBPA showed a homogeneous gene expression profile that was characterized by downregulation of HOX genes, whereas patients with moCEBPA showed greater heterogeneity in their gene expression profiles. Conclusion Biallelic disruption of the N and C terminus of CEBPA is required for the favorable clinical outcome of CEBPA-mutated patients and represents a distinct molecular subtype of CN-AML with a different frequency of associated gene mutations. These findings are of great significance for risk-adapted therapeutic strategies in AML.

scholarly journals Low expression of microRNA-204 (miR-204) is associated with poor clinical outcome of acute myeloid leukemia (AML) patients

2015 ◽  
Vol 34 (1) ◽  
Author(s):  
Aleksandra Butrym ◽  
Justyna Rybka ◽  
Dagmara Baczyńska ◽  
Andrzej Tukiendorf ◽  
Kazimierz Kuliczkowski ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Poor Clinical Outcome ◽  
Low Expression ◽  
Acute Myeloid

Prevalence and Prognostic Implications of WT1 Mutations in Pediatric AML Â: Report from Children’s Oncology Group

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 143-143 ◽  
Author(s):  
Jessica A Pollard ◽  
Rong Zeng ◽  
Phoenix Ho ◽  
Todd Alonzo ◽  
Robert Gerbing ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Wt1 Gene ◽  
Molecular Alterations ◽  
Microcapillary Electrophoresis ◽  
Pediatric Aml ◽  
Wbc Count ◽  
Wt1 Mutation

Abstract Molecular alterations of the WT1 gene have been associated with clinical outcome in adult AML. We evaluated the prevalence and prognostic significance of WT1 mutations in a cohort of 842 pediatric patients treated on pediatric AML trials CCG-2941, CCG-2961, or COG-AAML03P1. Exons 6–10 of the WT1 gene were evaluated by microcapillary electrophoresis and direct sequencing. Of the 842 samples diagnostic specimens analyzed, 68 (8%) contained mutations in exon 7 (n=62), exon 8 (n= 5), or exon 9 (n=1). Correlation analyses were done to determine whether the presence of WT1 mutations is associated with laboratory and disease characteristics and clinical outcome. There were no differences in sex, race, median diagnostic blast %, or median diagnostic WBC count between samples from patients carrying WT1 mutations and those from patients who did not; however, such mutations were less common in the younger patients (age, 0–2 years; p&lt;0.001) and in those with FAB M5 AML (p=0.009). Our evaluation of clinical outcome showed that the rate of complete remission after the first round of induction chemotherapy for those with and without WT1 mutations 74% and 80%, respectively (P=0.3) Actuarial overall survival (OS) from the time of study entry for patients with WT1 mutations was 35% vs. 52% for those without WT1 mutations; p=0.014. Corresponding event-free survival (EFS) was also significantly worse for those with WT1 mutations (27% vs. 41%; p=0.013). We also evaluated associations between WT1 mutations and cytogenetic and molecular alterations. In the patients with WT1 mutations, 31% had inv(16) or t(8;21). There was also substantial overlap between WT1 mutation and FLT3/ITD, i.e., 29% of those carrying a WT1 mutation were FLT3/ITD- positive, whereas only 7% of patients without WT1 were FLT3/ITD-positive (p&lt;0.001). In addition, 11q23 alterations were rare in patients with WT1 mutations (4% vs. 24%; p=0.002). Prognostic significance of WT1 mutations in FLT3/ITD-negative patients was determined. In a comparison of samples from FLT3/ITD-negative patients with WT1 mutations and those from patients who did not carry the 2 mutations, the OS (51% vs. 54%, respectively; p=0.5) and the corresponding EFS (34% and 43%, respectively; p=0.22) were not significantly different. The prognostic significance of the WT1 mutation was also determined in patients with a normal karyotype who were FLT3/ITD-negative. No significant differences were found in the OS (40% and 55%, respectively; p=0.23) or in the corresponding EFS values (31% and 45%, respectively; p=0.335). We conclude that about 8% of children with AML carry WT1 mutations, including novel mutations identified in exon 8. These mutations are associated with other cytogenetic and molecular alterations, and despite their overall association with poor outcome, the prognostic significance of WT1 mutations is less pronounced once the data are corrected for FLT3/ITD and cytogenetic abnormalities.

scholarly journals Acute Myeloid Leukemia With a Rare t(7;14)(q21;q32) and Trisomy 4 With Poor Clinical Outcome: A Case Report

2017 ◽  
Vol 48 (4) ◽  
pp. 376-380
Author(s):  
Seema B Jabbar ◽  
Sara Monaghan ◽  
Weina Chen ◽  
Prasad Koduru ◽  
Kirthi Kumar
Keyword(s):  
Acute Myeloid Leukemia ◽  
Case Report ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Poor Clinical Outcome ◽  
Acute Myeloid

scholarly journals IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marta Libura ◽  
Emilia Bialopiotrowicz ◽  
Sebastian Giebel ◽  
Agnieszka Wierzbowska ◽  
Gail J. Roboz ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Wild Type ◽  
Dna Hypermethylation ◽  
Isocitrate Dehydrogenase 1 ◽  
Mutation Status ◽  
Group 4 ◽  
Induction Regimen ◽  
Favorable Prognostic Factor

AbstractMutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients’ outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37–0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.

Clonal Involvement of the CD34+CD33− Progenitor Population by Leukemic Cells Harboring FLT3/ITD Correlates with High Risk of Relapse in Pediatric Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 227-227
Author(s):  
Jessica A. Wright ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
William G. Woods ◽  
Beverly J. Lange ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Poor Clinical Outcome ◽  
Free Survival ◽  
Allelic Ratio ◽  
Risk Of Relapse ◽  
Acute Myeloid

Abstract Internal tandem duplication of the FLT3 gene (FLT3/ITD) has been associated with high risk of relapse in acute myeloid leukemia (AML) yet nearly 25–30% of the patients with FLT3/ITD have long-term disease free survival with conventional chemotherapy. We hypothesized that FLT3/ITD AML patients with poor clinical outcome may have disease that involves less mature hematopoietic precursors than patients with favorable outcome. To test this hypothesis, we isolated less mature, CD34+CD33− and more mature, CD34+CD33+ precursor cells from 24 pediatric AML patients enrolled on Children’s Cancer Group clinical trials CCG-2891 and 2961 previously identified as having a FLT3/ITD. Granulocyte/monocyte colonies (CFU-GM) were grown in methylcellulose, harvested, and analyzed for the presence of FLT3/ITD after 14 days of growth. Twenty patients yielded sufficient cells and growth of CFU-GM colonies for analysis. FLT3/ITD was detected in CFU-GM colonies derived from CD34+CD33+ cells in all patient samples (median 80% of colonies tested per patient, range 6–100%). In contrast, FLT3/ITD was detected in CFU-GM colonies derived from CD34+/CD33− cells in only 11 of the 20 patient samples (median 46% of colonies tested per patient, range 6–100%). Of the 9 patient samples without FLT3/ITD involvement of CD34+CD33− colonies, 8 achieved a CR, 6 of whom are long-term survivors, and one patient died of non-leukemic causes. In contrast, of the 11 patients with CD34+CD33− cell involvement, 9 either failed to achieve CR or relapsed after achieving CR, and 2 died of non-leukemic causes. Actuarial progression-free survival at 4 years from diagnosis for the patients with and without FLT3/ITD in the CD34+CD33− population was 0% vs. 68% respectively (p=0.017). As allelic ratio of the FLT3/ITD has been used to define high-risk patients within the FLT3/ITD cohort, we determined the FLT3/ITD allelic ratio in our study population and correlated it with the presence of FLT3/ITD in the CD34+CD33− population. Ten of the 11 (91%) of the patient samples with FLT3/ITD involvement of the progenitor cells had high allelic ratio compared to 5 of 9 (56%) of the patients without early cell involvement. Together these data suggest that clonal dominance of FLT3/ITD containing leukemia cells at the CD34+CD33− stage of hematopoietic development is correlated with a high risk of relapse. Further studies are required to determine whether clonal dominance at this hematopoietic stage is a variable that, independent of high allelic ratio, accounts for the poor clinical outcome seen in a subset of FLT3/ITD positive AML patients.

Sign in / Sign up

Export Citation Format

Share Document