Gene mutations predominantly occurring in cytogenetically normal acute myeloid leukemia (AML).
| Gene . | Biological/clinical features . | Selected references . |
|---|---|---|
| Abbreviations: BM, bone marrow; LDH, lactate dehydrogenase; CN, cytogenetically normal; ITD, internal tandem duplication; TKD, tyrosine kinase domain; MRD, matched related donor; CR, complete remission; JM, juxtamembrane domain; UPD, uniparenteral disomy; OS, overall survival; RFS, relapse-free survival; EFS, event-free survival; PTD, partial tandem duplication. | ||
| NPM1 | Protein with pleiotropic functions | 18 |
| 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 | 6,10–15 | |
| Found in 25% to 35% of AML; predominantly in CN-AML (45% to 62%) Associated with FLT3-ITD and TKD mutations | 6,11,13,15 | |
| NPM1mut/FLT3-ITDneg genotype associated with a favorable prognosis | 10–12,15 | |
| Patients with NPM1mut/FLT3-ITDneg genotype may not benefit from MRD allogeneic transplantation in first CR | 10,37 | |
| FLT3 | Member of the class III receptor tyrosine kinase family Constitutively active FLT3 molecules are targets for molecular therapy | 26 |
| ITD | Found in 28% to 34% of CN-AML In-frame mutations, mostly in exons 14 and 15 of the JM domain | 3,6 |
| Consistently associated with inferior outcome | 22–25 | |
| Level of mutant allele likely of importance | 23,25 | |
| Homozygous FLT3 mutations as a result of mitotic recombination leading to partial UPD | 28,49 | |
| TKD | TKD point mutations found in 11% to 14% of CN-AML | 24,25,30 |
| More recently associated with better OS | 30 | |
| Level of mutant allele may be of importance: high-level mutants associated with improved OS | 30 | |
| CEBPA | Transcription factor mediating lineage specification and differentiation of multipotent myeloid progenitors into mature neutrophils | 31 |
| Found predominantly in CN-AML and AML with 9q deletion | 3,6 | |
| Associated with higher CR rate and better RFS and OS | 3,6 | |
| MLL | PTD found in 5% to 11% of CN-AML Associated with shorter CR duration, or inferior RFS and EFS | 6 |
| Autologous transplantation may improve outcome | 32 | |
| Rationale for the use of DNA methyltransferase and/or histone deacetylase inhibitors based on in vitro data | 33 | |
| RAS | NRAS mutations found in ~9% of CN-AML No prognostic significance | 6 |
| WT1 | Mutations found in ~10% of CN-AML Initial studies on small patient cohorts suggest association with induction failure | 7,34 |
| Gene . | Biological/clinical features . | Selected references . |
|---|---|---|
| Abbreviations: BM, bone marrow; LDH, lactate dehydrogenase; CN, cytogenetically normal; ITD, internal tandem duplication; TKD, tyrosine kinase domain; MRD, matched related donor; CR, complete remission; JM, juxtamembrane domain; UPD, uniparenteral disomy; OS, overall survival; RFS, relapse-free survival; EFS, event-free survival; PTD, partial tandem duplication. | ||
| NPM1 | Protein with pleiotropic functions | 18 |
| 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 | 6,10–15 | |
| Found in 25% to 35% of AML; predominantly in CN-AML (45% to 62%) Associated with FLT3-ITD and TKD mutations | 6,11,13,15 | |
| NPM1mut/FLT3-ITDneg genotype associated with a favorable prognosis | 10–12,15 | |
| Patients with NPM1mut/FLT3-ITDneg genotype may not benefit from MRD allogeneic transplantation in first CR | 10,37 | |
| FLT3 | Member of the class III receptor tyrosine kinase family Constitutively active FLT3 molecules are targets for molecular therapy | 26 |
| ITD | Found in 28% to 34% of CN-AML In-frame mutations, mostly in exons 14 and 15 of the JM domain | 3,6 |
| Consistently associated with inferior outcome | 22–25 | |
| Level of mutant allele likely of importance | 23,25 | |
| Homozygous FLT3 mutations as a result of mitotic recombination leading to partial UPD | 28,49 | |
| TKD | TKD point mutations found in 11% to 14% of CN-AML | 24,25,30 |
| More recently associated with better OS | 30 | |
| Level of mutant allele may be of importance: high-level mutants associated with improved OS | 30 | |
| CEBPA | Transcription factor mediating lineage specification and differentiation of multipotent myeloid progenitors into mature neutrophils | 31 |
| Found predominantly in CN-AML and AML with 9q deletion | 3,6 | |
| Associated with higher CR rate and better RFS and OS | 3,6 | |
| MLL | PTD found in 5% to 11% of CN-AML Associated with shorter CR duration, or inferior RFS and EFS | 6 |
| Autologous transplantation may improve outcome | 32 | |
| Rationale for the use of DNA methyltransferase and/or histone deacetylase inhibitors based on in vitro data | 33 | |
| RAS | NRAS mutations found in ~9% of CN-AML No prognostic significance | 6 |
| WT1 | Mutations found in ~10% of CN-AML Initial studies on small patient cohorts suggest association with induction failure | 7,34 |