Table 4.
Prototype of Gene Mutations Occurred in Cytogenetically Normal AML or in Cytogenetically Defined AML Subsets (~40–50% of Adult and 25% of Pediatric AML)
| Gene Mutations (Locations) | Biological and Clinical Features | Recommended Chemotherapy | Outcomes |
|---|---|---|---|
| NPM1(5q35) mutations | The most frequent genetic alteration in adult AML, mutated transcripts as MRD associated with a relapse and a lower rate of survival | Better response to induction & consolidation CC | Favorable outcome: (increased DFR, RFS and OS), achievement of CR |
| FLT3-ITD (13q12) mutations | A class III RTK, ITD in JM domain, constitutive activation of MAPK, STAT, and AKT/PI3K pathways, uncontrolled proliferation/survival of leukemic HPCs | CC + double TKi is recommended & promising | Inferior outcome/poor prognosis, especially depends on the high allelic ratio (the FLT3 mutant allele/FLT3 wild-type allele >0.5); which show shorter CR duration, DFS and OS |
| FLT3-TKD (13q12) mutations | Point mutations in TK domain, constitutive activation of the receptor | CC + double TKi eg midostaurin, crenolanib, gilteritinib | Negative/positive prognostic impact if being with NPM1 mutation |
| CEBPA(19q13) mutations | A master TF in hematopoiesis, mutations/its promoter hypermethylation decrease DNA-binding (leucine zipper domain) activity/its expression, mutually exclusive with NPM1 mutations | – | Double-mutations have a favorable outcome: higher CR duration, better RFS, OS, similar to those of mutant NPM1 |
| MLL-PTD (11q23) mutations | A DNA binding protein regulates hematopoiesis by epigenetics, cooperating with epigenetic factors (DNMTs & HDACs) | CC + HDACi (depsipeptide) + DNMTi (decitabine) reactivate the MLL wild-type allele & induce cell death of the blasts | Unfavorable outcome: shorter CR duration, inferior RFS & EFS, No effect on OS |
| RUNX1/AML1(21q22.3) mutations | A TF makes dimers with CBF-β for hematopoietic differentiation | – | Unfavorable outcome |
| KIT mutations | A class III RTK, a key role in proliferation & survival of hematopoietic progenitor cells, gain of function mutations, high frequency in t(8; 21), detected by allele specific PCR | CC + double TKi is recommended & promising | Inferior outcome, in particular in mutations of exon 17 |
| RAS (NRAS, KRAS)(1p13) mutations | Membrane-associated G proteins, transforming oncogene, high frequency in the favorable risk inv(16) or inv(3) group, NRAS/KRAS the most frequent | Sensitive to HDCA (post-remission HDAC) + farnesyl transferase inhibitor (tipifarnib, shuts down RAS) | Poor outcome |
| BAALC (8q22.3) over-expression | Associated with high percentage of blood blasts, immature subtypes M0/M1, monocytic differentiation, accompanied by FLT3-ITD, CEBPA, MLL-PTD mutations, high ERG expression, a marker of MDR | Induction failure, modulation of induction + intensification of post-remission + consolidation with allogeneic SCT | An adverse risk factor, unfavorable outcome: (low CR rates, high CIR, inferior OS (3 years)) |
| WT1(11p13) mutations | A TF is related to proliferation in hematopoietic progenitor cells, concurrent of FLT3-ITD, a marker of MRD, | Induction failure, modulation of induction + intensification of post-remission | Unfavorable; associated with induction failure |
| MN1 (22 q11) over-expression | Low MN1 expression responds to ATRA, high MN1 expression resistant to ATRA | Poor response to the first induction treatment, ATRA resistance in elderly | Unfavorable outcome: (short RFS) |
Note: Data from references 1–3,8, and 13.
Abbreviations: CC, conventional chemotherapy; MRD, minimal residual disease; RFS, relapse-free survival; OS, overall survival; CR, complete remission; EFS, event-free survival; CIR, cumulative incidence of relapse; DFS, disease-free survival; HPCs, hematopoietic progenitor cells; RTK, receptor tyrosine kinase; TF, transcription factor; FLT3, FMS-related tyrosine kinase 3; FLT3-ITD, internal tandem duplication of FLT3; TKD, tyrosine kinase domain; JM, juxtamembrane domain; MRD, matched related donor; PTD, partial tandem duplication; DNMTi, DNA methyltransferase inhibitor; CEBPA, CCAAT enhancer-binding protein gene; WT1, Wilms tumor gene; HDACi, histone deacetylase inhibitor; AT, transcription factor; CBF, core-binding-factor; BAALC, brain and acute leukemia cytoplasmic gene; MN1, meningioma1; SCT, stem-cell transplantation; MDR, multi-drug resistance, RUNX1, Runt-related transcription factor 1, HDAC, high-doses of cytarabine; HDACi, histone deacetylase inhibitor.