Acute myeloid leukemia with the t(8;21) translocation: clinical consequences and biological implications

Abstract

The t(8;21) abnormality occurs in a minority of acute myeloid leukemia (AML) patients. The translocation results in an in-frame fusion of two genes, resulting in a fusion protein of one N-terminal domain from the AML1 gene and four C-terminal domains from the ETO gene. This protein has multiple effects on the regulation of the proliferation, the differentiation, and the viability of leukemic cells. The translocation can be detected as the only genetic abnormality or as part of more complex abnormalities. If t(8;21) is detected in a patient with bone marrow pathology, the diagnosis AML can be made based on this abnormality alone. t(8;21) is usually associated with a good prognosis. Whether the detection of the fusion gene can be used for evaluation of minimal residual disease and risk of leukemia relapse remains to be clarified. To conclude, detection of t(8;21) is essential for optimal handling of these patients as it has both diagnostic, prognostic, and therapeutic implications.

Figure 1

Domain organization of the full-length and alternative AML1-ETO fusion proteins. (a) The full-length AML1-ETO (A1-E) protein is shown, where most of the ETO (RUNX1T1) gene is fused into the N-terminal 177aa of AML1 (RUNX1) gene giving rise to a transcript coding for a protein of 752 amino acids (aa). The AML1 gene encodes the Runt homology domain (RHD) which is a DNA-binding protein, while ETO encodes four highly conserved functional domains called nervy homology domains (NHR1-4). (b) Different fusion transcripts arise due to alternative exon usage and splicing, which give rise to truncated proteins lacking NHR domains. Protein size (i.e., number of aa) is shown on the right with the number of additional aa that were not included in the original sequence. These alternative A1-E transcripts can be coexpressed alongside the full-length transcript and have different leukemogenic capabilities.

Figure 2

Cytogenetic analysis of AML blasts by G-banding and FISH. (a) The derivative chromosomes from a simple reciprocal translocation between 8q22 and 21q22 are detectable by G-banding (upper panel) and the translocation can be verified using FISH probes (lower panel) against ETO and AML1. With this particular probe (Vysis LSI ETV6(TEL)/RUNX1(AML1) ES Dual Color) fusion signals will appear both on derivative 8 and derivative 22. (b) In rare cases, AML1-ETO fusion occurs as a result of insertion. Small insertions can only be detected using FISH probes. In this case, the translocation t(7;8)(q11;q22) between chromosome 7 and 8 and the 9q deletion del(9)(q12q22) were detected. As deletion 9q is rare in AML and can coexist with AML1-ETO fusion, FISH analysis was, therefore, performed. Only one fusion signal on derivative 22 was detected, indicating an ins(21;8)(q22;q22q22) insertion. (c) AML1 can also be involved in translocations with other partners mimicking complex t(8;21). In this case, there is a translocation between 9q22 and 21q22. FISH analysis using in-house split-signal probes against AML1 verified the involvement of these genes, whereas the gene on derivative 9 is unknown.

Figure 3

General architecture of the c-kit receptor and the mutations described in combination with the t(8;21) abnormality in the study by Wang et al. [30]. The c-kit type III receptor tyrosine kinase consists of an extracellular ligand-binding portion comprising five immunoglobulin-(Ig-) like repeats, a single transmembrane (TM) domain, a juxtamembrane domain (JMD), and a cytoplasmic portion containing and a split tyrosine kinase domain (TK1 and TK2) with a kinase insert sequence (KIS). Locations of c-kit abnormalities found in t(8;21) AML are indicated by the arrows. c-kit mutations are found more frequently within the extracellular fifth immunoglobulin-like domain (exon 8) and the second tyrosine kinase domain which contains the activation loop (exon 17).