Dissection of PIM serine/threonine kinases in FLT3-ITD-induced leukemogenesis reveals PIM1 as regulator of CXCL12-CXCR4-mediated homing and migration.
Dissection of PIM serine/threonine kinases in FLT3-ITD-induced leukemogenesis reveals PIM1 as regulator of CXCL12-CXCR4-mediated homing and migration.
复制标题
在FLT3-ITD诱导的白血病中解剖PIM丝氨酸/苏氨酸激酶，表明PIM1是CXCL12-CXCR4介导的归巢和迁移的调节剂。
DOI：
10.1084/jem.20082074
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发表时间：
2009-08-31
期刊：
影响因子：
--
通讯作者：
Schwaller J
中科院分区：
文献类型：
--
作者：
Grundler R;Brault L;Gasser C;Bullock AN;Dechow T;Woetzel S;Pogacic V;Villa A;Ehret S;Berridge G;Spoo A;Dierks C;Biondi A;Knapp S;Duyster J;Schwaller J
flt3 - itd介导的白血病发生与致癌PIM丝氨酸/苏氨酸激酶的表达增加有关。为了剖析它们在flt3 - itd介导的转化中的作用，我们进行了骨髓重建试验。出乎意料的是，缺乏PIM1的FLT3-ITD细胞未能重建致命的辐照受体，而缺乏PIM2诱导并不干扰FLT3-ITD诱导的疾病。pim1缺失的骨髓显示归巢和迁移缺陷，表面CXCR4表达减少，CXCL12-CXCR4信号通路受损。通过小干扰rna介导的敲除、化学抑制、显性阴性突变体的表达和/或敲除细胞中的再表达，我们发现PIM1活性对于CXCR4表面的适当表达和细胞向CXCL12梯度的迁移至关重要。纯化的PIM1导致体外CXCR4细胞内区域丝氨酸339的磷酸化，该区域已知对正常受体循环至关重要。在原发性白血病细胞中，高水平的表面CXCR4与PIM1表达增加相关，在一些患者中，一种小分子PIM抑制剂可以显著降低PIM1表达。我们的数据表明，PIM1活性通过修饰CXCR4对造血细胞的归巢和迁移很重要。由于CXCR4也调节癌症干细胞的归巢和维持，PIM1抑制剂可能部分通过干扰与微环境的相互作用来发挥其抗肿瘤作用。
FLT3-ITD–mediated leukemogenesis is associated with increased expression of oncogenic PIM serine/threonine kinases. To dissect their role in FLT3-ITD–mediated transformation, we performed bone marrow reconstitution assays. Unexpectedly, FLT3-ITD cells deficient for PIM1 failed to reconstitute lethally irradiated recipients, whereas lack of PIM2 induction did not interfere with FLT3-ITD–induced disease. PIM1-deficient bone marrow showed defects in homing and migration and displayed decreased surface CXCR4 expression and impaired CXCL12–CXCR4 signaling. Through small interfering RNA–mediated knockdown, chemical inhibition, expression of a dominant-negative mutant, and/or reexpression in knockout cells, we found PIM1 activity to be essential for proper CXCR4 surface expression and migration of cells toward a CXCL12 gradient. Purified PIM1 led to the phosphorylation of serine 339 in the CXCR4 intracellular domain in vitro, a site known to be essential for normal receptor recycling. In primary leukemic blasts, high levels of surface CXCR4 were associated with increased PIM1 expression, and this could be significantly reduced by a small molecule PIM inhibitor in some patients. Our data suggest that PIM1 activity is important for homing and migration of hematopoietic cells through modification of CXCR4. Because CXCR4 also regulates homing and maintenance of cancer stem cells, PIM1 inhibitors may exert their antitumor effects in part by interfering with interactions with the microenvironment.
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