In vitro and In vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells

• Published in: Blood Vol. 94; no. 7; pp. 2469 - 2476
• Main Authors: MAHGOUB, N, TAYLOR, B. R, GRATIOT, M, KOHL, N. E, GIBBS, J. B, JACKS, T, SHANNON, K. M
• Format: Journal Article
• Language: English
• Published: Washington, DC The Americain Society of Hematology 01.10.1999
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Division - drug effects; Cells, Cultured; Chemotherapy; Colony-Forming Units Assay; Crosses, Genetic; Farnesyltranstransferase; Female; Genes, Tumor Suppressor; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Leukemia, Myeloid; Leukocyte Count - drug effects; Liver - cytology; Liver - embryology; Male; Medical sciences; Methionine - analogs & derivatives; Methionine - pharmacology; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Neurofibromin 1; Pharmacology. Drug treatments; Protein Prenylation; Proteins - genetics; Proteins - metabolism; ras Proteins - metabolism; Antineoplastic agent; Human; Animal model; Enzyme; Transferases; Rodentia; Enzyme inhibitor; Malignant hemopathy; Inactivation; Farnesyl-diphosphate farnesyltransferase; In vitro; Myeloproliferative syndrome; In vivo; Vertebrata; Chemotherapy; Chronic; Mammalia; Treatment; Mouse; Animal; Chronic myelocytic leukemia; Established cell line; Genetics; Tumor suppressor gene
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v94.7.2469.419a01_2469_2476

Oncogenic RAS alleles encode proteins that accumulate in the guanosine triphosphate (GTP)-bound state. Because post-translational processing of Ras by farnesyltransferase is essential for biologic function, inhibitors of this enzyme have been developed as rational cancer therapeutics. We have investigated farnesyltransferase inhibitor (FTI) L-744,832 in an in vivo murine model of myeloid leukemia that is associated with inactivation of the Nf1 tumor suppressor gene. Nf1 encodes a GTPase activating protein for Ras, and Nf1-deficient (Nf1-/-) hematopoietic cells show hyperactive Ras signaling through the mitogen-activated protein (MAP) kinase pathway. L-744,832 inhibited H-Ras prenylation in cell lines and in primary hematopoietic cells and abrogated the in vitro growth of myeloid progenitor colonies in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). This FTI also partially blocked GM-CSF-induced MAP kinase activation, but did not reduce constitutively elevated levels of MAP kinase activity in primary Nf1-/- cells. Injection of a single dose of 40 or 80 mg/kg of L-744, 832 increased the amount of unprocessed H-Ras in bone marrow cells, but had no detectable effect on N-Ras. Adoptive transfer of Nf1-/- hematopoietic cells into irradiated mice induces a myeloproliferative disorder that did not respond to L-744,832 treatment. We speculate that the lack of efficacy in this model is due to the resistance of N-Ras and K-Ras processing to inhibition by this FTI.