Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors

Juvenile myelomonocytic leukemia (JMML) is an early childhood disease for w hich there is no effective therapy. Therapy with 13-cis retinoic acid or lo w-dose chemotherapy can induce some responses, but neither mode is curative , Stem cell transplantation can produce lasting remissions but is hampered by high rates of relapse. The pathogenesis of JMML involves deregulated cyt okine signal transduction through the Ras signaling pathway, with resultant selective hypersensitivity of JMML cells to granulocyte-macrophage colony- stimulating factor (GM-CSF). A JMML mouse model, achieved through homozygou s deletion of the neurofibromatosis gene, confirmed the involvement of dere gulated Ras in JMML pathogenesis, With this pathogenetic knowledge, mechani sm-based treatments are now being developed and tested, Ras is critically d ependent on a prenylation reaction for its signal transduction abilities. F arnesyltransferase inhibitors are compounds that were developed specificall y to block the prenylation of Pas. Two of these compounds, L-739,749 and L- 744,832, were tested for their ability to inhibit spontaneous JMML granuloc yte-macrophage colony growth, Within a dose range of 1 to 10 mu mol/L, each compound demonstrated dose-dependent inhibition of JMML colony growth. An age-matched patient with a different disease and GM-CSF-stimulated normal a dult marrow cells also demonstrated dose-dependent inhibitory effects on co lony growth, but they were far less sensitive to these compounds than JMML hematopoietic progenitors. Even if the addition of L-739,749 were delayed f or 5 days, significant inhibitory effects would still show in JMML cultures . These results demonstrate that a putative Ras-blocking compound can have significant growth inhibitory effects in vitro, perhaps indicating a potent ial treatment for JMML.