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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2503-2504. 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 Levis, M. Search for Related Content PubMed Articles by Levis, M. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL OBSERVATIONS Comment on Bacher et al, page 2527, andGale et al, page 2776 Who's dancing with FLT3? Mark Levis KIMMEL CANCER CENTER AT JOHNS HOPKINS UNIVERSITY FLT3 mutations may influence prognosis in acute myeloid leukemia (AML), but the context in which they occur may be just as important. Mutations of the receptor tyrosine kinase FLT3 are present in approximately 30% of patients with newly diagnosed AML.1 These mutations come in 2 forms, the first being the internal tandem duplication (FLT3/ITD) mutations, localized to the juxtamembrane region of the receptor, and the second being the point mutations located in the tyrosine kinase domain (FLT3/TKD). The FLT3/ITD mutations, which are the most common type, have clearly been shown to have a strong negative impact on clinical outcome, while the prognostic influence of an FLT3/TKD mutation is still uncertain. Several lines of laboratory data now suggest that FLT3 mutations by themselves do not cause AML.2 Rather, these mutations represent a single (albeit relatively common) event in a complex dance of mutations eventually leading to transformation. The interaction between the FLT3 mutation and other genetic lesions presumably influences the nature of the leukemia, which is reflected in its clinical behavior. In support of this concept, 2 articles in this issue of Blood provide evidence that the context in which these mutations occur influences their impact on patient prognosis. In the first report, by Gale and colleagues, leukemia DNA samples from 1425 patients enrolled on the United Kingdom Medical Research Council (MRC) AML 10 and 12 trials were analyzed for both FLT3 and nucleophosmin 1 (NPM1) mutations, and the results were compared with patient outcomes. Such a comparison has been performed by several other groups around the world, but the virtue of this particular MRC study lies in the large sample size and the resultant Kaplan-Meier curves. The findings confirm what others have suggested—namely, that when FLT3/ITD mutations dance without an NPM1 mutation, the prognosis is dismal, and when NPM1 mutations dance without an FLT3 mutation, the prognosis is better. When the 2 mutations dance a duet, the prognosis falls in the middle. The impact of FLT3/TKD mutations has been more difficult to discern, primarily because of their relatively low frequency in AML (5%-7% of cases). Bacher and colleagues present the results of a truly Herculean task, that of analyzing 3082 consecutive AML DNA samples from the German cooperative group trials for FLT3/ITD, FLT3/TKD, NPM1, NRAS, MLL, and CEBPA mutations. As with the work of Gale and colleagues, the sheer number of samples analyzed distinguishes this study from prior ones. Here, an FLT3/TKD mutation has an unfavorable effect when paired with an MLL mutation or a 15;17 translocation. Yet, when the FLT3/TKD mutation dances with an NPM1 mutation, the effect is favorable. Interestingly, the group from the United Kingdom previously re-ported a favorable influence of FLT3/TKD mutations in patients with core binding factor translocations.3 Thus, when FLT3 is engaged in the molecular danse macabre that leads to AML, the fate of the patient appears to depend on which dance partner it chooses. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Levis M and Small D. FLT3: ITDoes matter in leukemia. Leukemia 2003; 17:1738–1752.[CrossRef][Medline] [Order article via Infotrieve] Frohling S, Scholl C, Gilliland DG, Levine RL. Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol 2005; 23:6285–6295.[Abstract/Free Full Text] Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood 2007; 110:1262–1270.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients Ulrike Bacher, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach, and Susanne Schnittger Blood 2008 111: 2527-2537. [Abstract] [Full Text] [PDF] The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia Rosemary E. Gale, Claire Green, Christopher Allen, Adam J. Mead, Alan K. Burnett, Robert K. Hills, and David C. Linch, on behalf of the Medical Research Council Adult Leukaemia Working Party Blood 2008 111: 2776-2784. [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 Levis, M. Search for Related Content PubMed Articles by Levis, M. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?

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