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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1401-1402. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Grosveld, G. C. Search for Related Content PubMed Articles by Grosveld, G. C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Next Article  NEOPLASIA Comment on Heuser et al, page 1639 Treating AML with ATRA? Beware MN1! Gerard C. Grosveld SAINT JUDE CHILDREN'S RESEARCH HOSPITAL MN1 overexpression is a negative predictive factor for elderly AML patients receiving ATRA treatment. The paper by Heuser and colleagues in this issue of Blood identifies MN1 as a marker that predicts significantly prolonged event-free survival in elderly patients with acute myeloid leukemia (AML) who receive all-trans retinoic acid (ATRA). The MN1 gene encodes a transcriptional coactivator of the retinoic acid and vitamin D nuclear receptors.1 Patients with AML (except those with M3-AML) who expressed low levels of MN1 and received ATRA fared significantly better than those who did not receive ATRA or patients who expressed high levels of MN1 and did or did not receive ATRA. The authors also show that MN1 is an efficient myeloid oncoprotein; its overexpression in mouse bone marrow rapidly induced AML, suggesting the potential for a similar role in human AML. These observations are not the first to link MN1 with myeloid disease in humans. The MN1 gene was originally identified as the candidate meningioma tumor suppressor gene on chromosome 222 but is also the target of the balanced chromosome translocation t(12;22)(p13;q12) in human myeloid malignancies.3 MN1 is fused to TEL1 (ETV6), which encodes an ETS transcription factor. The MN1-TEL fusion protein exhibits oncogenic activity in primary mouse bone marrow cells and, in conjunction with HOXA9, predisposes mice to AML, a combination mimicking the situation in patients with t(12;22).4 MN1 overexpression was first noticed in the pediatric and adult M4-AML subtype, specified by the inv16 chromosomal aberration, which was confirmed by Carella et al.5 The encoded CBFb-MYH11 fusion gene is a dominant-negative regulator of the CBF transcription factor. In a paper published concurrently with the one discussed here, Carella and coworkers5 confirm MN1's oncogenicity in the mouse hematopoietic system and also show that MN1 overexpression strongly cooperates with CBFb-MYH11 in a mouse model of inv16 AML. Together, these data put MN1 firmly on the map of oncogenes to be reckoned with in human AML. View larger version (65K): [in this window] [in a new window]   Hypothetical model for MN1 function in myeloid progenitor cells. MN1 affects both differentiation and proliferation of myeloid progenitors. In this model, MN1 binds to the coactivator p300/CBP, which is (1) recruited to RAR/RXR target genes whose transcriptional repression inhibits differentiation. P300/CBP can also recruit MN1 to as-yet-unknown transcription factors (X) that (2) regulate genes affecting cell growth either by transcriptional activation (A) or repression (B).   How does MN1 work? Given that RAR/RXR recruits MN1 via the transcriptional coactivator p300/CBP,1 the article by Heuser and colleagues lifts a tip of the veil by showing that MN1 inhibits ATRA-induced differentiation of myeloid progenitors. Their data suggest that the differentiation block is caused by a dominant-negative effect of MN1 on RAR/RXR (see figure), which is released when MN1 is fused to the VP16 transcription-activating domain. Given that MN1-VP16 does not interfere with MN1's growth-promoting activity, growth might be mediated via other transcription factors. Through its interaction with p300/CBP, MN1 may affect the activity of multiple myeloid transcription factors that recruit p300/CBP, all of which help to regulate the growth and differentiation of myeloid progenitors (see figure). Therefore, to fully comprehend the role of MN1 in bone marrow and the detrimental effects of MN1 overexpression, extensive biochemical and biologic analyses are needed to identify these myeloid transcription factors. This, in turn, may lead to the design or discovery of substances that interfere with MN1's ability to interact with these transcription factors. The study by Heuser and colleagues strongly suggests that patients whose AML cells overexpress MN1 and are not responsive to ATRA treatment could greatly benefit from treatment with such substances. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES van Wely KH, Molijn AC, Buijs A, et al. The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription. Oncogene 2003; 22:699–709.[CrossRef][Medline] [Order article via Infotrieve] Lekanne Deprez RH, Riegman PH, Groen N. A, et al. Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma. Oncogene 1995; 10:1521–1528.[Medline] [Order article via Infotrieve] Buijs A, Sherr S, van Baal S, et al. Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11. Oncogene 1995; 10:1511–1519.[Medline] [Order article via Infotrieve] Kawagoe H and Grosveld GC. Conditional MN1-TEL knock-in mice develop acute myeloid leukemia in conjunction with overexpression of HOXA9. Blood 2005; 106:4269–4277.[Abstract/Free Full Text] Carella C, Bonten J, Sirma S, et al. MN1 overexpression is an important step in the development of inv(16) AML. Leukemia Prepublished on May 24, 2007, as DOI 10.1038/sj.leu.2404778.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML Michael Heuser, Bob Argiropoulos, Florian Kuchenbauer, Eric Yung, Jessica Piper, Stephen Fung, Richard F. Schlenk, Konstanze Dohner, Tanja Hinrichsen, Cornelia Rudolph, Axel Schambach, Christopher Baum, Brigitte Schlegelberger, Hartmut Dohner, Arnold Ganser, and R. Keith Humphries Blood 2007 110: 1639-1647. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Grosveld, G. C. Search for Related Content PubMed Articles by Grosveld, G. C. 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