Gene Mutation	Prevalence in CN-AML	Function	Prognostic Impact	Management strategy
NPM-1 (Nucleophosmin-1)	50%	Nuclear shuttle protein that is aberrantly located in cytoplasm in leukemic blasts	Favorable in absence of Flt3-ITD mutation, benefit in older population	Standard induction chemotherapy followed by 3-4 cycles of high-dose cytarabine. Benefit for ATRA + chemotherapy in patients with the NPM-1 mutation.
Flt-3 ITD (Fms-like tyrosine kinase internal tandem domain mutation)	20%	Class III receptor tyrosine kinase. Constitutively activated causing proliferation, survival and differentiation	Significantly worse than unmutated FLT-3. A higher ratio of mutant:wild type alleles predicts worse outcome	OS with allogeneic stem cell transplant equivalent to patients with wild-type FLT-3. New FLT-3 inhibitors currently in clinical trials.
CEBP-α (CCAAT/enhancer binding protein alpha)	15-19%	Transcription factor critical to granulocyte maturation	With biallelic mutations, benefit in OS and RFS equivalent to the favorable sub-group of AML	Standard induction therapy followed by repetitive cycles of high-dose cytarabine is first-line treatment option; patients may not benefit from allogeneic HSCT in first CR
c-kit	Only relevant in core binding factor leukemias, mutated or over-expressed in 15-20% of CBF-AML	The SCF receptor tyrosine kinase. Mutations results in constitutive activation	In patients with CBF-AML, greater probability of relapse following CR	Low-dose Ara-C (LDAC) with Imatinib in elderly with c-kit over-expression non-inferior to standard chemotherapy. NCT00850382 is currently looking at Dasatinib in combination with 7+3 in CBF-AML.
MLL	7-10%	Partial tandem duplication results in wild type allelic silencing by promoter DNA methylation and histone modifications	Shorter remission duration	Improved outcomes with stem cell transplant. Preclinical data suggest a therapeutic role of HDAC inhibitors and hypomethylating agents.
WT1	10%	transcriptional regulator	Inferior prognosis. Frequent coincident FLT3mutations	No impact on treatment at this time
RUNX	10%	Transcription factor	Chemotherapy resistant disease. Worse EFS, RFS and OS	Patients do better with allogeneic stem cell transplants
RAS	12-27%	Constitutively activating mutations in N-Ras and K-Ras, members of GTP-ase family	No prognostic significance	Patients benefit from high dose cytarabine consolidation. Consider MEK inhibitors on clinical trials in patients with Ras mutations
TET2	23%	Redced levels of 5-OH methylcytosine which is needed for DNA demethylation	Lower CR rate and shorter DFS among favorable-risk CN-AML in CALGB study. In AMLSG study, no prognostic impact.	None known
DNMT3A	20%	Reduced enzymatic activity of DNA methytransferase results in decreased DNA methylation	Independently predict shorter overall survival (OS)	Benefit from high dose anthracycline induction chemotherapy (90mg/m2 daunorubicin)
IDH1, IDH2	33%	Gain of function mutations allowing them to convert α-ketoglutarate to 2-hydroxy-glutarate, which is a competitive inhibitorof histone demthylases	Prognostic impact depends on molecular context. IDH mutations co-existent with NPM-1 are associated with a good prognosis.	None known