Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD
Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD
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DOI：
10.1038/sj.leu.2404883
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发表时间：
2007-11-01
期刊：
影响因子：
11.4
通讯作者：
Kitamura, T.
中科院分区：
文献类型：
--
作者：
Lu, Y.;Kitaura, J.;Kitamura, T.
转化生长因子-β（TGF-β）刺激的克隆-22（TSC-22）最初作为TGF-β诱导型基因分离。在这项研究中，我们确定TSC-22作为一个潜在的白血病抑制剂。在急性髓细胞白血病中经常发现两种类型的FMS样酪氨酸激酶-3（Flt 3）突变：Flt 3-TKD在与预后不良相关的质膜结构域中含有内部串联重复，Flt 3-TKD在激酶结构域中含有点突变。Flt 3-ITD-和Flt 3-TKD-转导的Ba/ F3细胞之间的基因表达谱的比较显示，Flt 3-TKD而非Flt 3-ITD对Flt 3的组成性激活上调了TSC-22的表达。重要的是，用Flt 3抑制剂PKC 412或Flt 3小干扰RNA处理降低了Flt 3-TKD转导细胞中TSC-22的表达水平。TSC-22的强制表达抑制了几种白血病细胞系的生长并加速了其向单核细胞的分化，特别是与分化诱导剂组合。另一方面，TSC-22的显性阴性形式加速Flt 3-TKD转导的32 Dcl的生长。3个细胞。总的来说，这些结果表明TSC-22是白血病治疗的可能靶点。
Transforming growth factor-beta (TGF-b)-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-TKD 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.