Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Scientific Background

AML is caused by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow and other tissues. It is a heterogeneous disease with and incidence of 2.7:100,000/year and a median age of 65. AML is characterized by a presence of at least 20% blasts in the bone marrow. AML should be considered after a cytogenetic or molecular genetic detection of certain genetic aberrations defined by the WHO (2008), regardless of the proportion of blasts. Detection of specific, clonal chromosome abnormalities can confirm the clinical suspected diagnosis and provide information regarding the subtype of the disease. Apart from translocations and inversions, specific point mutations may occur in certain genes. Therefore, a combination of cytogenetic, molecular cytogenetic and molecular genetic procedures and the conventional diagnostic procedures is currently considered to give the most accurate information.

AMLs with a translocation t(8;21)(q22;q22) and inv(16)(p13.1q22) or t(16;16)(p13.1;q22) are part of what is known as core-binding factor AMLs. The t(8;21)(q22;q22) is found in approx. 5% of all AML cases, predominantly in younger patients. Due to the translocation, the RUNX1-RUNX1T1 (AML1-ETO) fusion gene is generated. The inv(16)(p13.1q22) or t(16;16)(p13.1;q22) with formation of the CBFB-MYH11 fusion gene can be detected in approximately 5-8% of all AML cases. Both fusion genes can be analyzed by qRT-PCR  after the initial diagnosis and to detect minimal residual disease during treatment. The core-binding factor AML has been associated with a favorable prognosis. However, the detection of a KIT mutation may have a negative impact on the prognosis.

Approximately 5-8% of all AML cases are acute promyelocytic leukemia with translocation t(15;17) (q22;q12) and the resulting PML-RARA fusion gene and are associated with a favorable prognosis. These patients benefit from treatment with all-trans-retinoic acid (ATRA), which leads to maturation of the cells. The success of treatment can be monitored by qRT-PCR. However, approximately 35-45% of these patients exhibit mutations in FLT3, which seem to have a negative impact on the prognosis.

The translocation t(9;11)(p22;q23) with the MLLT3-MLL fusion gene occurs in approximately 9-12% of all pediatric and in 2% of all adult AML cases and has an intermediate prognosis. However, there are a couple of other translocations know that involve the MLL gene in 11q23. They include MLLT1 (ELN), MLLT19 (AF10), MLLT4 (AF6) and ELL.

With a frequency of 0.7-1.8%, the translocation t(6;9)(p23;q34) with the DEK-NUP214 fusion gene is rarer. In 69% of all pediatric cases and in 78% of all adult cases it is associated with a FLT3-ITD mutation and an unfavorable prognosis.

The translocation t(3;3)(q21;q26.2) or inv(3)(q21q26.2) with the fusion gene RPN-EVI1 can be detected in 1-2% of all AML cases and has been associated with an aggressive phenotype.

AMLs with cytogenetic abnormalities are distinguished from AML with gene mutations. According to WHO 2008, an analysis of the genes FMS-related tyrosine-kinase 3 (FLT3), nucleophosmin 1 (NPM1) and CCAAT/enhancer binding protein-α (CEBPA) should be carried out especially in AML patients with a normal karyotype.

FLT3 encodes for a tyrosine-kinase receptor which is involved in the differentiation and proliferation of the hematopoietic stem cell. Approximately 20-40% of all AML patients with a normal karyotype exhibit FLT3 mutations. They can be distinguished into two types: 75-80% are internal tandem duplications in the juxtamembrane domain (FLT3-ITD testing patent is hold by Invivoscribe (EP 0 959 132 B1), testing can be conducted via LabPMM LLC in the US or LabPMM GmbH in the EU) and 20-35% are mutations in the tyrosine-kinase domain (FLT3-TKD). FLT3 mutations are associated with an unfavorable prognosis. NPM1 encodes a nucleocytoplasmic shuttle protein and is mutated in approximately 1/3 of all AML cases, while CEBPA encodes a transcription factor and is mutated in 15-20% of all AML cases. Without an FLT3 mutation being present, mutations in one of these genes is associated with a favorable prognosis.

Mutations in ASXL1 and DNMT3A are considered independent, unfavorable prognostic factors for overall survival in AML. Mutations in ASXL1 are often found in patients in the intermediate-risk group, whereas mutations in DNMT3A are associated with M4 or M5 AML as well as mutations in FLT3, NPM1, IDH1, and IDH2. Mutations in BCOR, RUNX1 and TP53 in AML are associated with a reduced overall survival and reduced event-free survival as well. Mutations in TET2 seem to have an unfavorable influence on event-free survival in AML, especially in patients > 65 years of age and in patients in the favorable-risk group. Mutations in the GATA2 gene are associated with biallelic CEBPA mutations (biCEBPA) and could function as a marker to identify patients with a even more favorable prognosis in the subgroup of patients with a prognostic favorable biCEBPA mutated AML. Patients with mutations in WT1 and a cytogenetically normal karyotype represent a distinct subgroup with a poor response to therapy. Mutations in NRAS, KRAS, IDH1 and IDH2 seem to have an influence on the development of leukemia and could prospectively play a major role in the choice of an appropriate therapy. Mutations in IDH1 seem to have an unfavorable influence in cytogenetically normal AML with a low molecular genetic risk (NPM1/FLT3-ITD negative). Whereas the IDH2-R140 mutation seems to have no or a rather positive effect on prognosis in AML, the IDH2-R172 mutation is associated with an unfavorable course of the disease. Patients with a KRAS mutation may benefit from a higher dose of cytarabine (Ara-C).