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New targets for therapy in acute myeloid leukemia

Leukemia volume 17, pages 492–495 (2003)Cite this article

With increased understanding of the molecular events occurring during the development of acute myeloid leukemia (AML), the number of potential targets for therapy has also grown. These targets can be placed into three broad categories. First, there are the immediate consequences of the mutational events leading to AML, such as mutated FLT3 or RAS. A second broad category of targets are those adaptive nonmutational changes a leukemic cell must make in order to survive given the initial mutational event, for example, the increased expression of BCL2 seen in most AML samples. A third category of targets includes the cell surface antigens that distinguish AML cells from the normal hematopoietic stem cell.

Mutations in tyrosine kinase receptors occur in a substantial proportion of cases of AML. The most common abnormalities are in the FLT3 receptor tyrosine kinase, with internal tandem duplications found in 15–30% of cases of AML and point mutations seen in another 5–10%.1,2 Point mutations in C-FMS are found in 10–20% of cases of AML3 while various mutations in C-KIT are seen in 5–10% of cases.4 Given the frequency of FLT3 mutations in AML, this abnormality has generated a great deal of interest as a potential therapeutic target. Recent work suggests that both the internal tandem duplications and the point mutations of FLT3 seen in AML are activating. Such activation induces factor-independent proliferation of human hematopoietic cell lines, and an activated FLT3 receptor in transgenic mice produces a myeloproliferative syndrome.5 The fact that a mutant FLT3 in mice does not result in full-blown leukemia suggests that other genetic events, such as mutations in genes affecting differentiation, are also required for the development of overt AML.6 While one or another form of FLT3 mutation is found in 20–40% of AML cases, it appears to be more commonly seen in cases with t(15;17) and t(6;9), and only rarely seen with −7, −5, t(8;21), inversion (16) or with mutated RAS.7 Patients with FLT3 mutations generally present with a higher white count and, in most studies, have had a poorer overall outcome.7,8,9,10 The specific FLT3 mutation found at diagnosis is usually also present at relapse. The central role of FLT3 in the development of AML has led to a search for small-molecule inhibitors of FLT3 and at least four are currently in early clinical trials with results likely forthcoming soon.11,12,13,14 These agents include CEP-701, an indolocarbazole derivative; PKC-412, a staurosporine derivative; SU11248, an indolinone-based inhibitor; and CT53518, a compound in the piperazinyl quinazoline class. All four are thought to block ATP binding to FLT3. These small molecules induce apoptosis of human FLT3 positive AML cell lines and prolong survival in nude mouse models of FLT3 positive AML.

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  1. Fred Hutchinson Cancer Research Center and the University of Washington, School of Medicine, Seattle, WA, USA

    F R Appelbaum

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This paper is part of a series of keynote addresses to be published in Leukemia. They were presented at the Acute Leukemia Forum, San Francisco, 19 April 2002. Supported by an unrestricted educational grant from Immunex Corporation.

This work was supported, in part, by grant numbers CA-15704 and CA-18029 from the National Cancer Institute, National Institutes of Health, DHHS.

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Appelbaum, F. New targets for therapy in acute myeloid leukemia. Leukemia 17, 492–495 (2003). https://doi.org/10.1038/sj.leu.2402810

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