Genetic Biomarkers in Acute Myeloid Leukemia

Will the Promise of Improving Treatment Outcomes Be Realized?

Jay Yang; Charles A Schiffer


Expert Rev Hematol. 2012;5(4):395-407. 

In This Article

Molecular Prognostic Markers

Approximately 40–45% of patients with de novo AML have normal cytogenetics. Progress in the molecular characterization of AML has largely focused on this group of patients, and the findings show that the majority of CN-AML patients now have a detectable recurrent genetic mutation (Table 1).

CCAAT Enhancer-binding Protein-α

CCAAT enhancer-binding protein-α (CEBPA) is a transcription factor in which gene mutations result in a differentiation block in myeloid precursors.[26] AML with mutated CEBPA (CEBPA+) and AML with mutated NPM1 (NPM1+ ) have both been incorporated into the WHO classification of myeloid neoplasms as provisional entities.[27] Mutations in CEBPA are strongly associated with CN-AML, occurring in 8–19% of patients in this group.[28,29] The majority of patients with CEBPA mutations have a C-terminal mutation on one allele and a T-terminal mutation on the other.[30] More recent evidence has shown that AML with CEBPA double (or biallelic) mutations (CEBPA-DM), but not CEBPA with single mutations, is associated with a better prognosis, compared to those patients whose condition is related to wild-type alleles.[29,31,32] In addition, only the former group has a distinct gene expression profile, thereby supporting its place as a distinct clinicopathologic entity. Younger patients with biallelic mutations have long-term OSs of approximately 60%.


The NPM1 gene encodes for a shuttling protein that, when mutated, is aberrantly localized to the cytoplasm. NPM1 is mutated in approximately 35% of younger patients with AML and 50% of patients with CN-AML.[33,34] There is ample evidence that NPM1 is a founder gene in leukemogenesis:[35]NPM1 mutations are found in preleukemic hematopoietic stem cells,[36] are stable throughout the disease course and at relapse, are found in almost all of the cells in a leukemic population and have a distinct miRNA profile.[37]

NPM1-mutated (NPM1+) AML exhibits enhanced sensitivity to chemotherapy as evidenced by higher CR rates and longer relapse-free survivals. Reported long-term survival rates are in the range of 50% and are even higher if FLT3-internal tandem duplication (ITD) mutations are not present. Recent evidence shows that older patients with NPM1 mutations also have a more favorable prognosis with intensive chemotherapy.[37] In a report from the CALGB, patients older than 60 years of age with NPM1 + AML had CR rates of 84% and a 3-year OS of 35%, results that are far better than expected for this patient population. Thus, the presence of this mutation can help decide whether to administer intensive therapy to older patients with AML.


FLT3 is receptor tyrosine kinase that is expressed by immature hematopoietic cells and is mutated in approximately 25–30% of patients with AML, most often in those with normal karyotypes.[28,38,39] FLT3 mutations are usually the result of ITD of amino acids within the juxtamembrane domain of the receptor leading to its constitutive activation. Although FLT3 mutations are relatively common in AML, they are not classified as a unique entity in the WHO classification since they are also commonly seen in other types of AML, including APL and AML with t(6;9).[27]

FLT3-ITD is clinically associated with higher presenting blast counts, increased relapse rates from CR and poorer OSs. Previous reports had posited that the length of the ITD insertion may correlate with prognosis,[40] but recent studies have potentially clarified that FLT3 mutant levels, expressed as the allelic ratio of mutated to unmutated alleles, may be a more important factor.[41] The ITD can also have different insertion sites apart from the juxtamembrane domain, although the molecular and clinical relevance of this remains to be seen.[42,43]

Point mutations in the activating loop of the kinase domain (FLT3-TKD) are less common, seen in approximately 5% of AML[44] and 14% in CN-AML.[28]FLT3-TKD is associated with CN-AML, including those with NPM1 or CEBPA mutations. Although the data regarding its prognostic impact are conflicting,[28,45,46] most reports indicate that it has a less profound impact than the ITD. Some have suggested that the actual impact of the FLT3-TKD may depend on the whether or not the mutation is biallelic.[47]


Approximately 25% of patients with CBF leukemias will have a KIT mutation.[48] The most common is a D816V mutation, whereas mutations in exon 8 are less frequently seen. CBF leukemias with KIT mutations have a higher relapse rate resulting in a lower disease-free survival (DFS) and poorer OS, compared with their KIT wild-type counterparts.[49] It is unclear whether the location of the KIT mutation has any bearing on clinical outcomes, but in animal studies D816V is found to be more potent at activating KIT compared with mutations found at other sites.[50]