Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt

Abstract

We have developed a restriction map of the chromosome 21 breakpoint region involved in t(8;21)(q22;q22.3) acute myelogenous leukemia (AML) and have isolated a genomic junction clone containing chromosome 8 and 21 material. Using probes from these regions, rearrangements have been identified in each of nine cases of t(8;21) AML examined. In addition, we have isolated cDNA clones from a t(8;21) AML cDNA library that contain fused sequences from chromosome 8 and 21. The chromosome 8 component, referred to as ETO (for eight twenty-one), is encoded over a large genomic region, as suggested by the analysis of corresponding yeast artificial chromosomes (YACs). The DNA sequence of the chromosome 21 portion of the fusion transcript is derived from the normal AML1 gene. A striking similarity (67% identity over 387 bp, with a corresponding 69% amino acid identity) was detected between AML1 and the Drosophila segmentation gene, runt. The critical consequence of the translocation is the juxtaposition of 5′ sequences of AML1 to 3′ sequences of ETO, oriented telomere to centromere on the der(8) chromosome.

The Aml1‐eto Chimaeric Transcription Factor in Acute Myeloid Leukaemia: Biology and Clinical Significance

“…The 8;21 translocation was molecularly cloned in 1991 and shown to rearrange the AML1 gene (also referred to as CBFA2 or PEBP2aB) on chromosome 21q22 and the ETO gene (also referred to as MTG8) on chromosome 8q22 (Fig 1) (Miyoshi et al, 1991Erickson et al, 1992;Nisson et al, 1992). The AML1 gene encodes the DNA-binding subunit of the AML1/CBFb core binding factor transcription complex, whereas ETO encodes the mammalian homologue of the Drosophila protein Nervy (Feinstein et al, 1995).…”

“…Although t(8;21) is a balanced translocation in the majority of cases, rare AML cases with complex three-way (8;21;V) translocations have revealed that the der(8) chromosome, which encodes an AML1-ETO fusion protein is the critical genetic lesion (Rowley, 1982). The chromosomal breakpoints resulting from the t(8;21) cluster within a single intron of both AML1 and ETO and generate similar AML1-ETO chimaeric genes in every case (Erickson et al, 1992;Nucifora et al, 1993b;Maseki et al, 1993). The encoded fusion protein consists of the N-terminal 177 amino acids of AML1 fused in frame to almost the complete ETO protein (Fig 1).…”

Outcome and lineage involvement in t(12;21) childhood acute lymphoblastic leukaemia

“…This finding may indicate that the cellular target of the t(12;21) translocation can be represented by a more immature and multipotent progenitor rather than by an exclusively lymphoid-committed cell. Conversely, this data may simply reflect a different degree of functional disregulation of the AML1 gene, coding for a transcription factor involved both in lymphoid and myeloid differentiation Tanaka et al, 1995) and whose disruption is known to occur also in a high percentage of AML with the t(8;21) translocation (Myoshi et al, 1991;Erickson et al, 1992).…”

Cleavage of AML1/MTG8 by asymmetric hammerhead ribozymes

“…Injection of AML1/MTG8 RNA and ribozyme RNA into Xenopus eggs or oocytes causes a specific reduction of AML1/MTG8 protein expression. Asymmetric anti-AML1/MTG8 ribozymes may be valuable modulators of AML1/MTG8 expression in leukaemic cells.Keywords: catalytic RNA; RNA cleavage; acute myeloid leukaemia.The translocation t(8;21) is one of the most frequent chromosomal aberrations in acute myeloid leukaemia (AML) fusing the AML1 gene on chromosome 21 to the MTG8 gene on chromosome 8 [1,2]. This translocation replaces the C-terminal transactivation domain of AML1 by MTG8, the latter lacking only a few N-terminal amino acids.…”