Nature Medicine
- 12, 945 - 949 (2006)
Published online: 30 July 2006; | doi:10.1038/nm1443
A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesisMing Yan1, Eiki Kanbe1, Luke F Peterson1, Anita Boyapati1, Yuqin Miao2, Yang Wang1, I-Ming Chen3, Zixing Chen2, Janet D Rowley4, Cheryl L Willman3 & Dong-Er Zhang11
Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM-L51, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. 2
Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou 215006, China. 3
University of New Mexico Cancer Research and Treatment Center, University of New Mexico, 2325 Camino De Salud NE, Albuquerque, New Mexico 87131, USA. 4
Department of Medicine, University of Chicago, MC 2115, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA.
Correspondence should be addressed to Dong-Er Zhang dzhang@scripps.edu 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 subtypes1,
2,
3,
4. 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, CBF 2 or PEBP2B), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein5. 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 leukemia6,
7,
8,
9. 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.
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