Gene mutations occurring in cytogenetically normal acute myeloid leukemia
| Gene . | Incidence . | Biologic features . | Impact on clinical outcome and targeted therapy opportunities . |
|---|---|---|---|
| FLT3 | |||
| ITD | Found in 28%-34% of CN-AML | Member of the class III receptor tyrosine kinase family | Consistently associated with inferior outcome in terms of OS, RFS, and EFS33,34 |
| In-frame mutations, mostly in exons 14 and 15 of the juxtamembrane domain | Constitutively active FLT3 molecules are targets for specific molecular inhibitors (phase 2 or 3 trials) | ||
| Level of mutant allele probably of importance | |||
| Homozygous FLT3 mutations as a result of mitotic recombination leading to partial UPD | |||
| TKD | Found in 11%-14% of CN-AML | In-frame point mutations of the TKD codon 835 and 836 | Meta-analysis suggesting a negative prognostic impact32 |
| Level of mutant allele may be of importance | More recently associated with better OS31 | ||
| High-level mutants associated with improved OS30 | |||
| NPM1 | Found in 25%-35% of AML(45%-62% of CN-AML) | The mutational event modifies specific nucleoli binding and nuclear export signal motifs coded by the exon 12 and determines an abnormal cytoplasmic localization of nucleophosmin | NPM1mut/FLT3-ITD− genotype associated with a favorable OS, RFS, and CR rate38,39–40 |
| Associated with presenting clinical and laboratory features, such as female sex, higher BM blast counts, and LDH levels, as well as high CD33 but low or absent CD34 levels | Patients with NPM1mut/FLT3-ITD− genotype may not benefit from MRD allogeneic transplantation in first CR11 | ||
| Associated with FLT3-ITD and TKD mutations (40% of cases) | Pharmacologic modulation of the RA-signaling pathway has been suggested as a therapeutic option11 | ||
| NPM1 acts as a corepressor in RA-associated transcriptional regulation41 | |||
| CEBPA | Found in 15%-20% of CN-AML | Transcription factor mediating lineage specification and differentiation of multipotent myeloid progenitors into mature neutrophils | Associated with higher CR rate and better RFS and OS45,46 |
| Concurrent mutations (ie, FLT3-ITD and NPM1) were virtually not present in cases with CEBPA–biallelic mutation compared with CEBPA–single allelic mutation44 | The presence of CEBPA biallelic (bm) but not single allelic mutation (sm) is an independent factor for a favorable outcome44 | ||
| MLL | PTD found in 5%-11% of CN-AML | Usually involves exons 5-11 or, less frequently, exons 5-12 | Associated with shorter CR duration or inferior RFS and EFS60 |
| MLL wild-type allele is silenced, probably as a result of differential DNA methylation and histone modifications | Allogeneic transplantation may improve outcome11 | ||
| Rationale for the use of DNA methyltransferase and/or histone deacetylase inhibitors based on in vitro data | |||
| IDH1/2 | Found in 15% of AML | Correlated with accumulation of the cancer-associated metabolite 2-hydroxyglutarate | IDH1 mutations identify patients at higher risk of relapse within the favorable risk category of NPM1 mutated AML50,,–53 |
| IDH2 gene encodes a mitochondrial protein homologous to IDH1 that also catalyzes isocytratecarboxylation | IDH2 mutations get along with specific pretreatment features (low WBC, lack of other mutations, and primary resistance to chemotherapy)50,,–53 | ||
| IDH1 and IDH2 mutations are mutually exclusive | |||
| DNMT3A | Found in 22% of AML. | Somatic mutation in DNMT3A, encoding a DNA methyltransferase | Independent determinant of dismal prognosis both in the overall study population and, significantly, within high-risk patients (FLT3-ITD, age > 60 years)54 |
| Highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56/66, 33.7%) | Only ASCT provided a significant benefit54 | ||
| Absent in the subgroup of 79 patients carrying a favorable-risk cytogenetic | |||
| A perturbation in the methylation of specific DNA sequences has been postulated | |||
| BAALC overexpression | Rare | Expressed in neuroectoderm-derived tissues and hematopoietic precursors | Significantly worse CR rates and shorter DFS, EFS, and OS than patients with low expression55 |
| Detected in a subset of karyotypically normal adults < 60 years with de novo AML | SCT in first CR might overcome the adverse prognostic effect of high BAALC expression55 | ||
| ERG overexpression | Rare | Identified in CN-AML patients and patients with prognostically unfavorable complex karyotypes with cryptic amplification of chromosome | Significantly shorter OS and higher CIR56,57 |
| RAS | Found in 9%-13% of CN-AML | Constitutively activated by point mutations either in the GTP-binding domain (codon 12/13) or in the GTPase domain (codon 61) | A clear prognostic role could not be elucidated yet42 |
| Possible susceptibility blasts to FTIs | |||
| WT1 | Found in ∼ 10% of CN-AML | The majority of mutations in both studies were frameshift mutations of exon 7, whereas only one was identified in exon 9 | Initial studies on small patient cohorts suggest association with induction failure47,–49 |
| Gene . | Incidence . | Biologic features . | Impact on clinical outcome and targeted therapy opportunities . |
|---|---|---|---|
| FLT3 | |||
| ITD | Found in 28%-34% of CN-AML | Member of the class III receptor tyrosine kinase family | Consistently associated with inferior outcome in terms of OS, RFS, and EFS33,34 |
| In-frame mutations, mostly in exons 14 and 15 of the juxtamembrane domain | Constitutively active FLT3 molecules are targets for specific molecular inhibitors (phase 2 or 3 trials) | ||
| Level of mutant allele probably of importance | |||
| Homozygous FLT3 mutations as a result of mitotic recombination leading to partial UPD | |||
| TKD | Found in 11%-14% of CN-AML | In-frame point mutations of the TKD codon 835 and 836 | Meta-analysis suggesting a negative prognostic impact32 |
| Level of mutant allele may be of importance | More recently associated with better OS31 | ||
| High-level mutants associated with improved OS30 | |||
| NPM1 | Found in 25%-35% of AML(45%-62% of CN-AML) | The mutational event modifies specific nucleoli binding and nuclear export signal motifs coded by the exon 12 and determines an abnormal cytoplasmic localization of nucleophosmin | NPM1mut/FLT3-ITD− genotype associated with a favorable OS, RFS, and CR rate38,39–40 |
| Associated with presenting clinical and laboratory features, such as female sex, higher BM blast counts, and LDH levels, as well as high CD33 but low or absent CD34 levels | Patients with NPM1mut/FLT3-ITD− genotype may not benefit from MRD allogeneic transplantation in first CR11 | ||
| Associated with FLT3-ITD and TKD mutations (40% of cases) | Pharmacologic modulation of the RA-signaling pathway has been suggested as a therapeutic option11 | ||
| NPM1 acts as a corepressor in RA-associated transcriptional regulation41 | |||
| CEBPA | Found in 15%-20% of CN-AML | Transcription factor mediating lineage specification and differentiation of multipotent myeloid progenitors into mature neutrophils | Associated with higher CR rate and better RFS and OS45,46 |
| Concurrent mutations (ie, FLT3-ITD and NPM1) were virtually not present in cases with CEBPA–biallelic mutation compared with CEBPA–single allelic mutation44 | The presence of CEBPA biallelic (bm) but not single allelic mutation (sm) is an independent factor for a favorable outcome44 | ||
| MLL | PTD found in 5%-11% of CN-AML | Usually involves exons 5-11 or, less frequently, exons 5-12 | Associated with shorter CR duration or inferior RFS and EFS60 |
| MLL wild-type allele is silenced, probably as a result of differential DNA methylation and histone modifications | Allogeneic transplantation may improve outcome11 | ||
| Rationale for the use of DNA methyltransferase and/or histone deacetylase inhibitors based on in vitro data | |||
| IDH1/2 | Found in 15% of AML | Correlated with accumulation of the cancer-associated metabolite 2-hydroxyglutarate | IDH1 mutations identify patients at higher risk of relapse within the favorable risk category of NPM1 mutated AML50,,–53 |
| IDH2 gene encodes a mitochondrial protein homologous to IDH1 that also catalyzes isocytratecarboxylation | IDH2 mutations get along with specific pretreatment features (low WBC, lack of other mutations, and primary resistance to chemotherapy)50,,–53 | ||
| IDH1 and IDH2 mutations are mutually exclusive | |||
| DNMT3A | Found in 22% of AML. | Somatic mutation in DNMT3A, encoding a DNA methyltransferase | Independent determinant of dismal prognosis both in the overall study population and, significantly, within high-risk patients (FLT3-ITD, age > 60 years)54 |
| Highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56/66, 33.7%) | Only ASCT provided a significant benefit54 | ||
| Absent in the subgroup of 79 patients carrying a favorable-risk cytogenetic | |||
| A perturbation in the methylation of specific DNA sequences has been postulated | |||
| BAALC overexpression | Rare | Expressed in neuroectoderm-derived tissues and hematopoietic precursors | Significantly worse CR rates and shorter DFS, EFS, and OS than patients with low expression55 |
| Detected in a subset of karyotypically normal adults < 60 years with de novo AML | SCT in first CR might overcome the adverse prognostic effect of high BAALC expression55 | ||
| ERG overexpression | Rare | Identified in CN-AML patients and patients with prognostically unfavorable complex karyotypes with cryptic amplification of chromosome | Significantly shorter OS and higher CIR56,57 |
| RAS | Found in 9%-13% of CN-AML | Constitutively activated by point mutations either in the GTP-binding domain (codon 12/13) or in the GTPase domain (codon 61) | A clear prognostic role could not be elucidated yet42 |
| Possible susceptibility blasts to FTIs | |||
| WT1 | Found in ∼ 10% of CN-AML | The majority of mutations in both studies were frameshift mutations of exon 7, whereas only one was identified in exon 9 | Initial studies on small patient cohorts suggest association with induction failure47,–49 |
LDH indicates lactate dehydrogenase; CN, cytogenetically normal; TKD, tyrosine kinase domain; MRD, matched related donor; JM, juxtamembrane domain; UPD, uniparental disomy; EFS, event-free survival; PTD, partial tandem duplication; NPM1, nucleophosmin (nucleolar phosphoprotein B23, numatrin); FLT3-ITD, internal tandem duplication of the fms-related tyrosine kinase 3 (FLT3) gene; RA, retinoic acid; DFS, disease-free survival; CEBPA, CCAAT/enhancer binding protein (C/EBP)–α; CRD, CR duration; MLL-PTD, partial tandem duplication of the myeloid/lymphoid or mixed-lineage leukemia (MLL) gene; IDH1/2, isocitrate dehydrogenase 1 and 2; DNMT3A, DNA methyltransferase 3A gene; BAALC, brain and acute leukemia gene, cytoplasmic; ERG, v-erythroblastosis virus E26 oncogene-like (avian); GTP, guanosine triphosphate; and FTIs, farnesyltransferase inhibitors.