A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis.
The t(8;21)(q22;q22) translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in 15% of all cases of AML, including 40-50% of FAB M2 subtype and rare cases of M0, M1 and M4 subtypes. The most commonly known AML1-ETO fusion protein (full-length AML1-ETO) from this translocation has 752 amino acids and contains the N-terminal portion of RUNX1 (also known as AML1, CBFalpha2 or PEBP2alphaB), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein. Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia. Here, we report the identification of a previously unknown alternatively spliced isoform of the AML1-ETO transcript, AML1-ETO9a, that includes an extra exon, exon 9a, of the ETO gene. AML1-ETO9a encodes a C-terminally truncated AML1-ETO protein of 575 amino acids. Expression of AML1-ETO9a leads to rapid development of leukemia in a mouse retroviral transduction-transplantation model. More importantly, coexpression of AML1-ETO and AML1-ETO9a results in the substantially earlier onset of AML and blocks myeloid cell differentiation at a more immature stage. These results indicate that fusion proteins from alternatively spliced isoforms of a chromosomal translocation may work together to induce cancer development.
Yan
Ming
M
Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM-L51, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Kanbe
Eiki
E
Peterson
Luke F
LF
Boyapati
Anita
A
Miao
Yuqin
Y
Wang
Yang
Y
Chen
I-Ming
IM
Chen
Zixing
Z
Rowley
Janet D
JD
Willman
Cheryl L
CL
Zhang
Dong-Er
DE
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons; D006801:Humans; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000075142:RUNX1 Translocation Partner 1 Protein; D012190:Retroviridae / Q000235:genetics; D014178:Translocation, Genetic
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D000075142:RUNX1 Translocation Partner 1 Protein