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Blood, 15 July 2007, Vol. 110, No. 2, pp. 473-474. 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 Walter, M. J. Search for Related Content PubMed Articles by Walter, M. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Joslin et al, page 719 Del(5q): gene dosage matters Matthew J. Walter WASHINGTON UNIVERSITY SCHOOL OF MEDICINE In this issue of Blood, Joslin and colleagues provide new evidence that EGR1 haploinsufficiency may contribute to myeloid diseases associated with loss of a whole chromosome 5 or a deletion of the long arm, del(5q). Del(5q) is one of the most common cytogenetic abnormalities found in de novo and therapy-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The potential importance of del(5q) as an early or initiating genetic event in MDS is highlighted by the sensitivity of del(5q) clones (occurring either alone or with complex karyotypes) to treatment with lenalidomide.1 Over the past decade, work by Le Beau2 and others has implicated haploinsufficiency of a gene or genes on chromosome 5q31, rather than homozygous deficiency for a gene, as a mechanism for pathogenesis. Recent evidencesupporting this hypothesis suggests that reduced expression of CTNNA1, a gene on the del(5q) interval, is important in del(5q)-associated MDS and AML.3 Now, Joslin and colleagues demonstrate that haploinsufficiency of Egr1, another gene on the human del(5q) interval, plays a role in the development of myeloid disease in mice. Joslin and colleagues thoroughly characterized the hematopoiesis of Egr1 heterozygous and homozygous knock-out mice under normal physiologic conditions, which showed no differences compared with wild-type mice. The authors went on to treat Egr1 mutant mice with a single dose of N-ethyl-nitrosourea (ENU), a prototypical alkylating agent, in order to induce secondary cooperating mutations. ENU-treated Egr1+/– and Egr1–/– mice both developed T-cell lymphomas and a myeloproliferative disease (MPD) at higher frequencies than ENU-treated wild-type mice (see figure). The MPD phenotype resembles the MDS/MPD overlap disease of humans. Thus, the data suggest that loss of 1 copy of Egr1 contributes to myeloid disease in mice by cooperating with unidentified, ENU-induced mutations. View larger version (42K): [in this window] [in a new window]   Survival curves of mice treated with ENU (includes T-cell lymphoma, MPD, and other causes). See the complete figure in the article beginning on page 719.   The identification of critical genes in the 5q31 region that contribute to MDS or AML has been hampered by the difficulty of studying haploinsufficiency as a mechanism of disease pathogenesis. This study elegantly explores the effect of gene haploinsufficiency, but also highlights the difficulty of modeling myeloid diseases in mice. Although myeloid disease was only minimally increased in Egr1+/– mice treated with ENU, it is possible that the contribution of Egr1 haploinsufficiency to myeloid disorders is underestimated due to the propensity of this mouse strain (C57BL/6) to develop lymphomas when treated systemically with ENU.4 In addition, ENU treatment predominantly induced an MPD phenotype in these mice rather than MDS or AML, which may also be modified by studying Egr1 haploinsufficiency in a mouse strain susceptible to ENU-induced AML and MDS.3 Although the mechanism of disease initiation in Egr1-haploinsufficient hematopoietic cells is unknown, there is precedent for Egr1 behaving as a tumor suppressor in other cancer models. This study adds to the growing list of genes implicated in hematologic malignancies that act as tumor suppressors in the haploinsufficient state. Importantly, the findings also raise the possibility that decreased expression of multiple del(5q) genes may be necessary for disease initiation, and highlight the need to develop whole-genome approaches to identify additional cooperating mutations in MDS and AML in mice and humans. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355:1456–1465.[Abstract/Free Full Text] Lai F, Godley LA, Joslin J, et al. Transcript map and comparative analysis of the 1.5-Mb commonly deleted segment of Human 5q31 in Malignant Myeloid Diseases with a del(5q). Genomics 2001; 71:235–245.[CrossRef][Medline] [Order article via Infotrieve] Liu TX, Becker MW, Jelinek J, et al. Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nat Med 2007; 13:78–83.[CrossRef][Medline] [Order article via Infotrieve] Fenske TS, McMahon C, Edwin D, et al. Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice. Cancer Res 2006; 66:5029–5038.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders John M. Joslin, Anthony A. Fernald, Thelma R. Tennant, Elizabeth M. Davis, Scott C. Kogan, John Anastasi, John D. Crispino, and Michelle M. Le Beau Blood 2007 110: 719-726. [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 Walter, M. J. Search for Related Content PubMed Articles by Walter, M. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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