Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD

Y. Lu, J. Kitaura, T. Oki, Y. Komeno, K. Ozaki, M. Kiyono, H. Kumagai, H. Nakajima, T. Nosaka, H. Aburatani, T. Kitamura

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Transforming growth factor-β (TGF-β)-stimulated clone-22 (TSC-22) was originally isolated as a TGF-β-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.

Original languageEnglish (US)
Pages (from-to)2246-2257
Number of pages12
JournalLeukemia
Volume21
Issue number11
DOIs
StatePublished - Nov 2007

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Lu, Y., Kitaura, J., Oki, T., Komeno, Y., Ozaki, K., Kiyono, M., Kumagai, H., Nakajima, H., Nosaka, T., Aburatani, H., & Kitamura, T. (2007). Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD. Leukemia, 21(11), 2246-2257. https://doi.org/10.1038/sj.leu.2404883