AML moleculair diagnostics

RUNX1-RUNXT1
The RUNX1-RUNXT1 gene fusion transcript is frequently found amongst adult patients with de novo acute myeloid leukemia. The incidence amongst AML is approximately 6-8%. Patients with this fusion transcript have a relatively favorable prognosis. In most cases the fusion can also be cytogenetically observed as a translocation between chromosome 8 and 21 [t(8;21)].

CBFB-MYH11
The CBFB-MYH11 fusion gene is found in approximately 6-8% of cases with acute myeloid leukemia. Patients with this fusion have a relatively good prognosis and are treated accordingly. Molecular screening for CBFB-MYH11 is strongly recommended as the chromosomal rearrangements causing this fusion [the inv(16)(p13q22) and t(16;16)(p13;q22)] can be missed by routine cytogenetic analysis.

FLT3 ITD
Fms-like tyrosine kinase 3 (FLT3) is a tyrosine kinase receptor which is activated upon binding of FLT3 ligand. FLT3 internal tandem duplications (ITDs) are present in approximately 20% of AML patients and result in constitutive activation of FLT3. The ITDs are present in part of the juxtamembrane of the protein (exons 14 and 15). The FLT3 ITDs are associated with an unfavorable prognosis in AML.

FLT3 TKD
Fms-like tyrosine kinase 3 (FLT3) is a tyrosine kinase receptor which is activated upon binding of FLT3 ligand. Both FLT3 and its ligand are expressed in normal progenitor cells as well as in precursor B-ALL and AML cells. FLT3 internal tandem duplications (ITDs) are present in approximately 20% of AML patients. Besides FLT3 ITDs point mutations in FLT3 codon 835 are present in approximately 5% of AML. Whether the codon 835 mutations are associated with a poor prognosis remains controversial. However, patients with FLT3 codon 835 benefit from FLT3 inhibitors such as Midostaurin.

CEBPA mutation
The CEBPA (CCAAT/enhancer binding protein alpha) gene encodes a transcription factor essential for myeloid differentiation. CEBPA mutations can be found in about 5 to 10 percent of de novo AML and in 13 to 19 percent of patients with cytogenetically normal AML. Two types of CEBPA mutations are predominantly seen, i.e., N-terminal frame-shift mutations and C-terminal in-frame insertions or deletions. CEBPA mutations are association with a favorable outcome. The favorable effect of CEBPA mutations is limited to patients who carry double mutations in CEBPA (either two different mutations or one homozygous mutation).

ASXL1 mutation
Somatic mutations in the additional sex comb-like 1 (ASXL1) gene have been described in various types of myeloid malignancies, including AML (app. 10%) and correlated to an adverse outcome. In addition, ASXL1 mutations are found in age-related clonal hematopoiesis. The Polycomb Group (PcG) and trithorax Group (trxG) proteins are epigenetic regulators. PcG proteins are required to epigenetically silence their target genes, whereas trxG proteins maintain transcriptional activation. ASXL1 belongs to the Enhancer of trithorax and Polycomb genes, which are responsible for maintaining activation and silencing of PcG and trxG proteins.

TP53 mutation
Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. The transcription factor TP53 plays a role in regulation or progression through the cell cycle, apoptosis, and genomic stability. TP53 is thought to be a tumor suppressor in AML and mutations that deactivate p53 in cancer usually occur in the DBD. In AML, TP53 is affected by mutations or deletions in app. 10% of cases and associated with a dismal outcome.