Flt3 inhibitor AC220 is a potent therapy in a mouse model of myeloproliferative disease driven by enhanced wild-type Flt3 signaling

Blood. 2012 Nov 8;120(19):4049-57. doi: 10.1182/blood-2012-06-436675. Epub 2012 Sep 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiazoles / administration & dosage
  • Benzothiazoles / pharmacology*
  • Cell Cycle / drug effects
  • Cell Proliferation
  • Disease Models, Animal
  • Female
  • Humans
  • Leukocyte Count
  • Leukocytes / drug effects
  • Liver / pathology
  • Lung / pathology
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Multipotent Stem Cells / drug effects
  • Multipotent Stem Cells / metabolism
  • Mutation
  • Myeloid Cells / pathology
  • Myeloproliferative Disorders / drug therapy
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / metabolism*
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / pharmacology*
  • Proto-Oncogene Proteins c-cbl / genetics
  • Signal Transduction / drug effects*
  • Splenomegaly / drug therapy
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / metabolism*

Substances

  • Benzothiazoles
  • Membrane Proteins
  • Phenylurea Compounds
  • flt3 ligand protein
  • quizartinib
  • Proto-Oncogene Proteins c-cbl
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3