title: Flt3 inhibitor AC220 is a potent therapy in a mouse model of myeloproliferative disease driven by enhanced wild-type Flt3 signaling.
abstract: High levels of expression of wild-type Flt3 characterize many hematopoietic proliferative diseases and neoplasms, providing a potential therapeutic target. Using the c-Cbl RING finger mutant mouse as a model of a myeloproliferative disease (MPD) driven by wild-type Flt3, in the present study, we show that treatment with the Flt3 kinase inhibitor AC220 blocks MPD development by targeting Flt3(+) multipotent progenitors (MPPs). We found that daily administration of AC220 caused a marked reduction in Flt3 expression, induction of quiescence, and a significant loss of MPPs within 4 days. Unexpectedly, a robust Flt3 ligand-associated proliferative recovery response soon followed, preventing further loss of MPPs. However, continued AC220 treatment limited MPP recovery and maintained reduced, steady-state levels of cycling MPPs that express low levels of Flt3. Therefore, a finely tuned balance between the opposing forces of AC220 and Flt3 ligand production was established; whereas the Flt3 ligand blunted the inhibitory effects of AC220, the disease was held in remission for as long as therapy was continued. The net effect is a potent therapy indicating that patients with c-Cbl mutations, or those with similarly enhanced Flt3 signaling, may respond well to AC220 even after the induction of high levels of Flt3 ligand.
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Taylor
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Dagger
authors.forename: Christine B F
authors.initials: CB
authors.lastname: Thien
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wikstrom
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D022423:Myeloid Cells / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013163:Splenomegaly / Q000188:drug therapy; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D008565:Membrane Proteins; D010671:Phenylurea Compounds; C084881:flt3 ligand protein; C544967:quizartinib; D050721:Proto-Oncogene Proteins c-cbl; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3