Effects of MLN518, a dual FLT3 and KTT inhibitor, on normal and malignant hematopoiesis

Ian J. Griswold, Lei J. Shen, Paul La Rosée, Shadmehr Demehri, Michael Heinrich, Rita Braziel, Laura McGreevey, Andrea D. Haley, Neill Giese, Brian Druker, Michael W N Deininger

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (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 platelet-derived growth-factor receptor (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 with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate 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.

Original languageEnglish (US)
Pages (from-to)2912-2918
Number of pages7
JournalBlood
Volume104
Issue number9
DOIs
StatePublished - Nov 1 2004
Externally publishedYes

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Hematopoiesis
Protein-Tyrosine Kinases
Leukemia
Chemotherapy
Acute Myeloid Leukemia
Drug Therapy
tandutinib
Receptor Protein-Tyrosine Kinases
Hematopoietic Stem Cells
Bone Marrow Transplantation
Toxicity
Assays
Bone
Phosphotransferases
Stem Cells
Transplantation
Chemical activation
Mutation
Molecules
Growth

ASJC Scopus subject areas

  • Hematology

Cite this

Griswold, I. J., Shen, L. J., La Rosée, P., Demehri, S., Heinrich, M., Braziel, R., ... Deininger, M. W. N. (2004). Effects of MLN518, a dual FLT3 and KTT inhibitor, on normal and malignant hematopoiesis. Blood, 104(9), 2912-2918. https://doi.org/10.1182/blood-2003-05-1669

Effects of MLN518, a dual FLT3 and KTT inhibitor, on normal and malignant hematopoiesis. / Griswold, Ian J.; Shen, Lei J.; La Rosée, Paul; Demehri, Shadmehr; Heinrich, Michael; Braziel, Rita; McGreevey, Laura; Haley, Andrea D.; Giese, Neill; Druker, Brian; Deininger, Michael W N.

In: Blood, Vol. 104, No. 9, 01.11.2004, p. 2912-2918.

Research output: Contribution to journalArticle

Griswold, IJ, Shen, LJ, La Rosée, P, Demehri, S, Heinrich, M, Braziel, R, McGreevey, L, Haley, AD, Giese, N, Druker, B & Deininger, MWN 2004, 'Effects of MLN518, a dual FLT3 and KTT inhibitor, on normal and malignant hematopoiesis', Blood, vol. 104, no. 9, pp. 2912-2918. https://doi.org/10.1182/blood-2003-05-1669
Griswold, Ian J. ; Shen, Lei J. ; La Rosée, Paul ; Demehri, Shadmehr ; Heinrich, Michael ; Braziel, Rita ; McGreevey, Laura ; Haley, Andrea D. ; Giese, Neill ; Druker, Brian ; Deininger, Michael W N. / Effects of MLN518, a dual FLT3 and KTT inhibitor, on normal and malignant hematopoiesis. In: Blood. 2004 ; Vol. 104, No. 9. pp. 2912-2918.
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abstract = "Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (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 platelet-derived growth-factor receptor (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 with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate 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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AU - Heinrich, Michael

AU - Braziel, Rita

AU - McGreevey, Laura

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