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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1752. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Carroll, M. Search for Related Content PubMed Articles by Carroll, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Krejci et al, page 2190 New role for AML1/ETO in leukemogenesis Martin Carroll UNIVERSITY OF PENNSYLVANIA The AML1/ETO fusion protein induces DNA double-strand breaks, p53 expression, and a DNA damage response, suggesting a new role in AML pathogenesis. In this issue of Blood, Krejci and colleagues suggest that the transcription factor fusion protein, AML1/ETO (also known as RUNX1/MTG8), which is known to block differentiation in myeloid cells, may also increase DNA damage, adding to its functions in leukemogenesis. The AML1/ETO fusion protein was originally identified 15 years ago as the protein product of the t(8;21) translocation associated with M2 acute myeloid leukemia (AML).1 The protein acts as a transcriptional regulator by recruitment of nuclear corepressors leading to inhibition of the core binding factor complex, which includes the AML1 protein.2 This inhibition leads to a block in myeloid differentiation, but in vivo, AML1/ETO expression is not sufficient to generate acute leukemia.3 In their article, Krejci and colleagues study the expression of AML1/ETO in primary human CD34 cells. They demonstrate that cells expressing AML1/ETO induce expression of a DNA damage response that is p53 dependent, and suggest that the induction of a p53 response is associated with improved prognosis of t(8;21)+ AML. The authors use retroviral constructs to express AML1/ETO in primary human CD34+ cells. As they have previously demonstrated,4 expression of AML1/ETO "immortalizes" these cells so that they can be studied over the course of several weeks in culture. Consistent with previous results,5 they make the observation that AML1/ETO expression leads to transcriptional down-regulation of genes involved in base excision repair of DNA damage, particularly the genes 8-oxoguanine glycosylase gene (OGG1), and polymerase epsilon gene (POLE).5 Importantly, they demonstrate that binding of AML1/ETO is through a RUNX1 binding site, suggesting that regulation of DNA damage-response genes may be a physiologic function of RUNX1. Curiously, although base excision repair is primarily involved in the repair of point mutations in DNA, the authors then demonstrate that AML1/ETO-expressing cells have an increase in DNA double-strand breaks and an up-regulation of p53 expression. Down-regulation of p53 expression with a siRNA approach in AML1/ETO-expressing cells makes the cells more sensitive to ionizing radiation and other DNA-damaging agents. Overall, the study makes a convincing argument that AML1/ETO expression leads to an altered response to spontaneous and induced DNA damage. How are we to interpret these data in the context of a growing body of data about the multiplicity of functions of AML1/ETO and data about the role of DNA damage responses in hematologic malignancies? The answer to this is unknown, but the data do not support the idea that oncogenes such as AML1/ETO are simple stimulators of cell growth. If these complex proteins lead to development of a "super cell," they do so by inducing the cells to develop mechanisms to survive stress (a transforming boot camp of sorts). Expression of AML1/ETO actually induces apoptosis in some cells.6 The presence of DNA double-strand breaks in these cells may represent the induction of replication stress and DNA breaks during S phase. The data leave unanswered the question of the necessity of this DNA damage-induced stress response for cellular transformation. However, the well-described structure of the AML1/ETO fusion may allow for structure-function studies that will better define the necessities and sufficiencies for transformation induced by this fascinating oncoprotein. Footnotes Conflict-of-interest disclosure: The author received financial support from Cephalon Oncology, West Chester, PA. REFERENCES Erickson P, Gao J, Chang KS, et al. 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. Blood 1992; 80:1825–1831.[Abstract/Free Full Text] Lutterbach B, Westendorf JJ, Linggi B, et al. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol 1998; 18:7176–7184.[Abstract/Free Full Text] Yuan Y, Zhou L, Miyamoto T, et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci U S A 2001; 98:10398–10403.[Abstract/Free Full Text] Mulloy JC, Jankovic V, Wunderlich M, et al. AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion. Proc Natl Acad Sci U S A 2005; 102:4016–4021.[Abstract/Free Full Text] Alcalay M, Meani N, Gelmetti V, et al. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J Clin Invest 2003; 112:1751–1761.[CrossRef][Medline] [Order article via Infotrieve] Burel SA, Harakawa N, Zhou L, Pabst T, Tenen DG, Zhang DE. Dichotomy of AML1-ETO functions: growth arrest versus block of differentiation. Mol Cell Biol 2001; 21:5577–5590.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death Ondrej Krejci, Mark Wunderlich, Hartmut Geiger, Fu-Sheng Chou, David Schleimer, Michael Jansen, Paul R. Andreassen, and James C. Mulloy Blood 2008 111: 2190-2199. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Carroll, M. Search for Related Content PubMed Articles by Carroll, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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