publication . Other literature type . Article . 2016

Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML

Mohammed Dany; Salih Gencer; Rose Nganga; Raquela J Thomas; Natalia Oleinik; Kyla D Baron; Zdzislaw M Szulc; Peter Ruvolo; Steven Kornblau; Michael Andreeff; ...
Open Access English
  • Published: 13 Oct 2016
  • Publisher: American Society of Hematology
Abstract
Signaling pathways regulated by mutant Fms-like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD), which mediate resistance to acute myeloid leukemia (AML) cell death, are poorly understood. Here, we reveal that pro-cell death lipid ceramide generation is suppressed by FLT3-ITD signaling. Molecular or pharmacologic inhibition of FLT3-ITD reactivated ceramide synthesis, selectively inducing mitophagy and AML cell death. Mechanistically, FLT3-ITD targeting induced ceramide accumulation on the outer mitochondrial membrane, which then directly bound autophagy-inducing light chain 3 (LC3), involving its I35 and F52 residues, to recruit autophagosomes for exe...
Subjects
Medical Subject Headings: hemic and lymphatic diseasesembryonic structureshemic and immune systems
free text keywords: Myeloid Neoplasia, Immunology, Cell Biology, Biochemistry, Hematology, Molecular biology, Signal transduction, Mitochondrial fission, Mitophagy, Ceramide binding, Programmed cell death, Protein kinase A, Ceramide, chemistry.chemical_compound, chemistry, Biology, Small hairpin RNA
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publication . Other literature type . Article . 2016

Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML

Mohammed Dany; Salih Gencer; Rose Nganga; Raquela J Thomas; Natalia Oleinik; Kyla D Baron; Zdzislaw M Szulc; Peter Ruvolo; Steven Kornblau; Michael Andreeff; ...