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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4109-4110.
Next Article 
NEOPLASIA
Comment on Fazi et al, page 4432
AML1/ETO, a promiscuous fusion oncoprotein
Kevin Petrie, and
Arthur Zelent
INSTITUTE OF CANCER RESEARCH
In this issue of Blood, Fazi and colleagues demonstrate that ligand-activated transcription via retinoic acid receptor  , which is important for proper myelomonocytic differentiation, is blocked by the AML1/ETO fusion oncoprotein.
Approximately 15% of all acute myeloid leukemia (AML) cases and up to 40% of those classified by the French-American-British system as M2 subtype harbor the t(8;21) translocation that gives rise to the AML1/ETO fusion oncoprotein (also known as RUNX1/MTG8). AML1/ETO consists of the N-terminal DNA-binding domain of AML1, a transcription factor essential for definitive hematopoiesis, and almost all of ETO, a protein thought to function as a corepressor for a variety of transcription factors. Initially, a simple model of AML1/ETO function in leukemogenesis reflected only its dominant-negative effects on AML1 target genes, in large part via the aberrant recruitment of epigenetic modifiers such as histone deacetylases and DNA methyltransferases. However, phenotypic differences between the AML1-null mouse model and a knockin for AML1/ETO pointed to other activities of this oncoprotein besides deregulation of AML1 target genes. We now know that AML1/ETO impacts multiple processes involved in normal myelomonocytic development where the fusion protein interferes with multiple signal transduction pathways, promoting early myeloid cell self-renewal and interfering with proper hematopoietic differentiation.1 AML1/ETO also directly interferes with recruitment of essential cofactors by a number of crucial hematopoietic transcription factors such as C/EBP and PU.1, thus potentially blocking their differentiation-promoting functions (see figure).
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AML1/ETO promiscuously targets and blocks the activities of RXR/RAR and other hematopoietic transcription factors. Different functional domains of the AML1/ETO fusion protein are indicated as follows: the Runt DNA-binding domain (DBD) of the AML1 moiety; a region that shares homology with TAF110 and other related TAF proteins; a heptad repeat of hydrophobic amino acids (HHR); a region that shares homology with Drosophila nervy protein; and a C-terminal region containing 2 nonclassical zinc fingers. Positions of indicated transcription factors relative to AML1/ETO do not reflect regions of interaction with the fusion protein.
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In this issue of Blood, Fazi and colleagues demonstrate that another important signaling pathway that positively regulates myelomonocytic differentiation is disrupted by AML1/ETO. They show that the AML1/ETO fusion oncoprotein recruits an array of negatively acting epigenetic factors to a model all-trans-retinoic acid (ATRA) target gene promoter, RARß2, via direct interaction with retinoic acid receptor alpha (RAR; see figure). Of interest, siRNA knockdown of AML1/ETO relieves repression of the RARß2 promoter, pointing to a critical role for the fusion protein in silencing RARß2 in this context. RAR binds its cognate response element as a heterodimer with RXR, and in the absence of ligand (ATRA) recruits a multiprotein corepressor complex to inhibit transcription. Ligand binding to RAR causes a conformational change leading to exchange of corepressor proteins for coactivator complexes and activation of gene transcription.2 The data presented by Fazi et al indicate that AML1/ETO may interfere directly with RAR function by binding to the receptor in a ligand-independent manner, thus also blocking the ability of ATRA to mediate coregulator exchange and preventing activation of RAR target gene expression. It remains to be seen whether AML1/ETO interacts with other nuclear receptors, but given its positive role in stem/progenitor cell self-renewal, it is interesting to speculate that AML1/ETO may also act upon a closely related RAR family member, RAR , which has been shown to be critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.3
So, what is the relevance of these findings for AML therapy? This study further underlines the importance of developing optimized combinatorial therapies that target multiple facets of the biologic activities of a given oncoprotein. In the case of AML1/ETO-associated AML, this study provides a rationale for the use of drugs such as eriocalyxin B and oridonin,4 which specifically degrade AML1/ETO, combined with differentiation therapy (ATRA and myelomonocytic growth factors). Drugs that reverse epigenetic modifications that negatively regulate gene expression, such as histone deacetylase and DNA methylation inhibitors, have been used in combination with ATRA to treat relapsed and therapy-resistant AML with encouraging results.5 This study highlights the possibility that t(8;21)-positive AML patients may represent a particularly suitable target population for this type of epigenetic/differentiation therapy and further investigation in this area is warranted.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests. 
REFERENCES
- Elagib KE and Goldfarb AN. Oncogenic pathways of AML1-ETO in acute myeloid leukemia: multifaceted manipulation of marrow maturation. Cancer Lett Prepublished on November 27, 2006, as DOI 10.1016/j.canlet.2006.10.010.
- Glass CK and Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 2000; 14:121–141.[Free Full Text]
- Purton LE, Dworkin S, Olsen GH, et al. RARgamma is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation. J Exp Med 2006; 203:1283–1293.[Abstract/Free Full Text]
- Zhou GB, Kang H, Wang L, et al. Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood Prepublished on December 29, 2006, as DOI 10.1182/blood-2006-06-032250.[Abstract/Free Full Text]
- Zelent A, Petrie K, Lotan R, Waxman S, Gore SD. Clinical translation of epigenetics in cancer: eN-CORe, a report on the second workshop. Mol Cancer Ther 2005; 4:1810–1819.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia
- Francesco Fazi, Giuseppe Zardo, Vania Gelmetti, Lorena Travaglini, Alberto Ciolfi, Luciano Di Croce, Alessandro Rosa, Irene Bozzoni, Francesco Grignani, Francesco Lo-Coco, Pier Giuseppe Pelicci, and Clara Nervi
Blood 2007 109: 4432-4440.
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