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Acute Leukemias

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

Leukemia volume 21, pages 2246–2257 (2007)Cite this article

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.

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Acknowledgements

We thank Dr Hitoshi Kawamata for providing plasmid pEGFP-TSC-22-LZ. We thank Dr Naoko Watanabe, Dr Yoshinori Yamanishi, Dr Kumi Izawa and Dr Yukinori Minoshima for valuable discussions, Fumi Shibata, Miyuki Ito and Ai Hishiya for excellent technical assistance. We also thank R&D Systems for cytokines. This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Technology, Sports, and Culture in Japan.

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  1. Divisions of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

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

  2. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

    H Aburatani

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Correspondence to T Kitamura.

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Lu, Y., Kitaura, J., Oki, T. et al. Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD. Leukemia 21, 2246–2257 (2007). https://doi.org/10.1038/sj.leu.2404883

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