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Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations.

Loghavi S, Zuo Z, Ravandi F, Kantarjian HM, Bueso-Ramos C, Zhang L, Singh RR, Patel KP, Medeiros LJ, Stingo F, Routbort M, Cortes J, Luthra R, Khoury JD - J Hematol Oncol (2014)

Bottom Line: DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026).Within mutation subgroups, patients with AML DNMT3A/NPM1 had a significantly shorter OS compared to those with AML FLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

View Article: PubMed Central - PubMed

ABSTRACT

Background: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AML DNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.

Methods: We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AML DNMT3A/FLT3/NPM1 patients.

Results: Patients with AML DNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AML DNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AML DNMT3A/NPM1 had a significantly shorter OS compared to those with AML FLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.

Conclusions: DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

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Schematic representation of mutations. (a) Mutation status of genes assessed in all patients in the study group. Each column represents an individual case. The bottom rows represent, respectively, the cytogenetic risk group (CG) and mutation group (MG) per corresponding color designation. Assessed genes in which mutations were not detected are not included in this diagram. Mutation detection techniques in the MDACC and TCGA groups were different (see Methods section). (b) Distribution of genomic variants within DNMT3A detected in the study group. PWWP represents a region encoding for a highly conserved proline-tryptophan-tryptophan-proline motif. ZNF represents the ADD (ATRX, DNMT3, and DNMT3L)-type zinc finger domain.
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Fig2: Schematic representation of mutations. (a) Mutation status of genes assessed in all patients in the study group. Each column represents an individual case. The bottom rows represent, respectively, the cytogenetic risk group (CG) and mutation group (MG) per corresponding color designation. Assessed genes in which mutations were not detected are not included in this diagram. Mutation detection techniques in the MDACC and TCGA groups were different (see Methods section). (b) Distribution of genomic variants within DNMT3A detected in the study group. PWWP represents a region encoding for a highly conserved proline-tryptophan-tryptophan-proline motif. ZNF represents the ADD (ATRX, DNMT3, and DNMT3L)-type zinc finger domain.

Mentions: A summary of mutations in genes assessed in both the MDACC and TCGA groups is provided in Figure 2a. All DNMT3A variants detected in patients with AMLDNMT3A/FLT3/NPM1 were missense substitutions in exon 23, and most involved codon 882 resulting in the substitution of arginine by histidine (14/35; 40%) or cysteine (14/35; 40%). Mutations in other codons - 882 (arginine > serine), 901 (leucine > proline), 874 (tyrosine-stop), 803 (arginine to serine), 855 (lysine to threonine) and 723 (frameshift) - were detected with less frequency. (Figure 2b) (Additional file 2: Table S1).Figure 2


Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations.

Loghavi S, Zuo Z, Ravandi F, Kantarjian HM, Bueso-Ramos C, Zhang L, Singh RR, Patel KP, Medeiros LJ, Stingo F, Routbort M, Cortes J, Luthra R, Khoury JD - J Hematol Oncol (2014)

Schematic representation of mutations. (a) Mutation status of genes assessed in all patients in the study group. Each column represents an individual case. The bottom rows represent, respectively, the cytogenetic risk group (CG) and mutation group (MG) per corresponding color designation. Assessed genes in which mutations were not detected are not included in this diagram. Mutation detection techniques in the MDACC and TCGA groups were different (see Methods section). (b) Distribution of genomic variants within DNMT3A detected in the study group. PWWP represents a region encoding for a highly conserved proline-tryptophan-tryptophan-proline motif. ZNF represents the ADD (ATRX, DNMT3, and DNMT3L)-type zinc finger domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197326&req=5

Fig2: Schematic representation of mutations. (a) Mutation status of genes assessed in all patients in the study group. Each column represents an individual case. The bottom rows represent, respectively, the cytogenetic risk group (CG) and mutation group (MG) per corresponding color designation. Assessed genes in which mutations were not detected are not included in this diagram. Mutation detection techniques in the MDACC and TCGA groups were different (see Methods section). (b) Distribution of genomic variants within DNMT3A detected in the study group. PWWP represents a region encoding for a highly conserved proline-tryptophan-tryptophan-proline motif. ZNF represents the ADD (ATRX, DNMT3, and DNMT3L)-type zinc finger domain.
Mentions: A summary of mutations in genes assessed in both the MDACC and TCGA groups is provided in Figure 2a. All DNMT3A variants detected in patients with AMLDNMT3A/FLT3/NPM1 were missense substitutions in exon 23, and most involved codon 882 resulting in the substitution of arginine by histidine (14/35; 40%) or cysteine (14/35; 40%). Mutations in other codons - 882 (arginine > serine), 901 (leucine > proline), 874 (tyrosine-stop), 803 (arginine to serine), 855 (lysine to threonine) and 723 (frameshift) - were detected with less frequency. (Figure 2b) (Additional file 2: Table S1).Figure 2

Bottom Line: DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026).Within mutation subgroups, patients with AML DNMT3A/NPM1 had a significantly shorter OS compared to those with AML FLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

View Article: PubMed Central - PubMed

ABSTRACT

Background: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AML DNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.

Methods: We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AML DNMT3A/FLT3/NPM1 patients.

Results: Patients with AML DNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AML DNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AML DNMT3A/NPM1 had a significantly shorter OS compared to those with AML FLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.

Conclusions: DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

Show MeSH
Related in: MedlinePlus