Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD.
Transforming growth factor-beta (TGF-beta)-stimulated clone-22 (TSC-22) was originally isolated as a TGF-beta-inducible gene. In this study, we identified TSC-22 as a potential leukemia suppressor. Two types of FMS-like tyrosine kinase-3 (Flt3) mutations are frequently found in acute myeloid leukemia: Flt3-ITD harboring an internal tandem duplication in the juxtamembrane domain associated with poor prognosis and Flt3-TKD harboring a point mutation in the kinase domain. Comparison of gene expression profiles between Flt3-ITD- and Flt3-TKD-transduced Ba/F3 cells revealed that constitutive activation of Flt3 by Flt3-TKD, but not Flt3-ITD, upregulated the expression of TSC-22. Importantly, treatment with an Flt3 inhibitor PKC412 or an Flt3 small interfering RNA decreased the expression level of TSC-22 in Flt3-TKD-transduced cells. Forced expression of TSC-22 suppressed the growth and accelerated the differentiation of several leukemia cell lines into monocytes, in particular, in combination with differentiation-inducing reagents. On the other hand, a dominant-negative form of TSC-22 accelerated the growth of Flt3-TKD-transduced 32Dcl.3 cells. Collectively, these results suggest that TSC-22 is a possible target of leukemia therapy.
Lu
Y
Y
Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kitaura
J
J
Oki
T
T
Komeno
Y
Y
Ozaki
K
K
Kiyono
M
M
Kumagai
H
H
Nakajima
H
H
Nosaka
T
T
Aburatani
H
H
Kitamura
T
T
D000818:Animals; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D012097:Repressor Proteins / Q000627:therapeutic use*; D020298:U937 Cells; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry* / Q000276:immunology
D012097:Repressor Proteins; C099726:TSC22D1 protein, human; C490983:Tgfb1i4 protein, mouse; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3