Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts

Abstract

Nonrandom and somatically acquired chromosomal translocations can be identified in nearly 50% of human acute myeloid leukemias. One common chromosomal translocation in this disease is the 8q22;21q22 translocation. It involves the AML1 (RUNX1) gene on chromosome 21 and the ETO (MTG8, RUNX1T1) gene on chromosome 8 generating the AML1-ETO fusion proteins. In this review, we survey recent advances made involving secondary mutational events and alternative t(8;21) transcripts in relation to understanding AML1-ETO leukemogenesis.

Figure 1

The 8;21 chromosomal translocation. (A) A chromosome preparation of a t(8;21) patient depicting normal chromosome 8, a shorter chromosome 8 with the translocated chromosome 21 (left arrow), normal chromosome 21, and a longer chromosome 21 fused to the portion of chromosome 8 (right arrow). The image was kindly provided by Dr Janet Rowley. (B) Genomic structure of t(8;21). Depicted are the exons of both AML1 and ETO organized following the reciprocal translocation. The first 5 exons of AML1 are fused to exons 2 through 11 of ETO. P1 and P2 with the horizontal arrows denote the start sites of transcription based on the usage of the distal (P1) or proximal (P2) promoters of AML1. The reciprocal ETO-AML1 fusion shows exons 1b and 1a of ETO fused to exons 6 through 12 of AML1. Filled boxes and blank boxes indicate translated and untranslated exon sequences, respectively. (C) Protein structure of AML1-ETO. As explained in the text, the commonly known full-length AML1-ETO protein is a 752-amino acid protein. The N-terminal portion of AML1 up to its runt homology domain (RHD) is fused to most of the ETO protein. Shown are the regions of homology to the Drosophila Nervy protein (NHR1 to NLH4) and 3 proline-serine-threonine-rich (PST) regions. The vertical arrow points to the fusion junction between AML1 and ETO.

Figure 2

Other possible AML1-ETO fusion proteins from reported alternate transcripts. Shown are other known alternative AML1-ETO predicted gene products identified in cell lines and patient samples aligned to the full-length fusion protein. The vertical arrow points to the fusion junction between AML1 and ETO. RHD indicates runt homology domain; NHR1 to NLH4, Drosophila Nervy protein homology regions; and PST, proline-serine-threonine-rich regions. References identifying these alternative products are indicated.

Figure 3

Diagram of the multistep leukemogenesis process associated with t(8;21). This model shows that after the initial event of t(8;21) within the hematopoietic stem cells (HSC) or multipotential progenitor (MPP), the cells will initially expand by the stem cell renewal program induced by the AML1-ETO fusion proteins associated with a block in myeloid differentiation. The loss of DNA repair mechanisms elicited by AML1-ETO creates an ideal environment for the acquisition of additional transforming mutagenic events such as FLT3 and Ras or deregulation of the NCoR/SMRT pathway. However, the appearance of alternative splice variants such as AML1-ETO9a may contribute to the speed of transformation or may even cooperate with AML1-ETO, being itself a secondary event by deregulated alternative splicing. The expression of AML1-ETO isoforms may also further aid in the gain and/or loss of genomic material often observed in t(8;21) leukemia through the deregulation of the mitotic checkpoint.