title: Flt3 receptor inhibition reduces constitutive NFkappaB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia.
abstract: High-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by the activation of the anti-apoptotic transcription factor NFkappaB, via the IKK complex. Here, we show that constitutive activation of the receptor tyrosine kinase Flt3 is responsible for IKK activation. Chemical inhibition or knockdown of Flt3 with small interfering RNAs reduced NFkappaB activation in MDS and AML cell lines, as well as in primary CD34(+) bone marrow cells from patients, causing apoptosis. Epistatic analysis involving the simultaneous inhibition of Flt3 and IKK suggested that both kinases act in the same anti-apoptotic pathway. An IKK2 mutant with a constitutive kinase activity and a plasma membrane-tethered mutant of NEMO that activates IKK1/2 prevented the cytocidal action of Flt3 inhibition. Flt3 phosphorylates IKK2 in vitro, and Flt3 inhibition reduced the phosphorylation of IKK2 in MDS or AML cell lines. IKK2 and Flt3 physically associated in MDS and AML cells, and Flt3 inhibition disrupted this interaction. Flt3 inhibition only killed CD34(+) bone marrow cells from high-risk MDS and AML patients, in correlation with blast numbers and NFkappaB activity, yet had no lethal effect on healthy CD34(+) cells or cells from low-risk MDS. These results suggest that Flt3 inhibitors might exert an anti-neoplastic effect in high-risk MDS and AML through inhibition of NFkappaB.
authors.affiliation: INSERM, U848, Institut Gustave Roussy, PR1, 38 rue Camille Desmoulins, 94805 Villejuif, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Grosjean-Raillard
authors.forename: Lionel
authors.initials: L
authors.lastname: Adès
authors.forename: Simone
authors.initials: S
authors.lastname: Boehrer
authors.forename: Maximilien
authors.initials: M
authors.lastname: Tailler
authors.forename: Claire
authors.initials: C
authors.lastname: Fabre
authors.forename: Thorsten
authors.initials: T
authors.lastname: Braun
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Botton
authors.forename: Alain
authors.initials: A
authors.lastname: Israel
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D004843:Epistasis, Genetic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D016328:NF-kappa B; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051550:I-kappa B Kinase