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Blood, 1 November 2004, Vol. 104, No. 9, pp. 2912-2918.
Prepublished online as a Blood First Edition Paper on July 8, 2004; DOI 10.1182/blood-2003-05-1669.
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Submitted May 29, 2003
Accepted June 18, 2004
Effects of MLN518, A Dual FLT3 and KIT Inhibitor, on Normal and Malignant Hematopoiesis
Ian J Griswold, Lei J Shen, Paul LaRosee, Shadmehr Demehri, Michael C Heinrich, Rita M Braziel, Laura McGreevey, Andrea D Haley, Neill Giese, Brian J Druker, and Michael W Deininger*
Oregon Health and Science University Cancer Institute, Portland, Oregon, USA; Howard Hughes Medical Institute, USA
Oregon Health and Science University Cancer Institute, Portland, Oregon, USA
III. Medizinische Universitaetsklinik, Fakultat fur klinische Medizin Mannheim der Universitat Heidelberg, Heidelberg, Germany
Oregon Health and Science University Cancer Institute, Portland, Oregon, USA; Portland VA Medical Center, Portland, Oregon, USA
Department of Pathology, Oregon Health and Science University Cancer Institute, Portland, Oregon, USA
Millenium Pharmaceuticals, San Francisco, California, USA
* Corresponding author; email: deininge{at}ohsu.edu.
Internal tandem duplications (ITD) of the FLT3 receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT and PDGFR tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady state conditions, after chemotherapy-induced myelosuppression and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared to ITD-negative AML patients, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib in BCR-ABL-positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
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