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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4392-4398.
Prepublished online as a Blood First Edition Paper on February 6, 2007; DOI 10.1182/blood-2006-03-012575.
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NEOPLASIA
The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO
Luke F. Peterson1,
Ming Yan1, and
Dong-Er Zhang1
1 Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA
The 8;21 translocation is a major contributor to acute myeloid leukemia (AML) of the M2 classification occurring in approximately 40% of these cases. Multiple mouse models using this fusion protein demonstrate that AML1-ETO requires secondary mutagenic events to promote leukemogenesis. Here, we show that the negative cell cycle regulator p21WAF1 gene is up-regulated by AML1-ETO at the protein, RNA, and promoter levels. Retroviral transduction and hematopoietic cell transplantation experiments with p21WAF1-deficient cells show that AML1-ETO is able to promote leukemogenesis in the absence of p21WAF1. Thus, loss of p21WAF1 facilitates AML1-ETO–induced leukemogenesis, suggesting that mutagenic events in the p21WAF1 pathway to bypass the growth inhibitory effect from AML1-ETO–induced p21WAF1 expression can be a significant factor in AML1-ETO–associated acute myeloid leukemia.
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