The multi-kinase inhibitor dasatinib has been implicated to be effective in pre-B-cell receptor (pre-BCR)-positive acute lymphoblastic leukemia (ALL) expressing the E2A-PBX1 fusion oncoprotein. The TGFβ signaling pathway is involved in a wide variety of cellular processes, including embryonic development and cell homeostasis, and it can have dual roles in cancer: suppressing tumor growth at early stages and mediating tumor progression at later stages. In this study, we identified the upregulation of the TGFβ signaling pathway in our previously generated human dasatinib-resistant pre-BCR+/E2A-PBX1+ALL cells using global transcriptomic analysis. We confirm the upregulation of the TGFβ pathway member SMAD3 at the transcriptional and translational levels in dasatinib-resistant pre-BCR+/E2A-PBX1+ALL cells. Hence, dasatinib blocks, at least partially, TGFβ-induced SMAD3 phosphorylation in several B-cell precursor (BCP) ALL cell lines as well as in dasatinib-resistant pre-BCR+/E2A-PBX1+ALL cells. Activation of the TGFβ signaling pathway by TGF-β1 leads to growth inhibition by cell cycle arrest at the G0/G1 stage, increase in apoptosis and transcriptional changes of SMAD-targeted genes, e.g. c-MYC downregulation, in pre-BCR+/E2A-PBX1+ ALL cells. These results provide a better understanding about the role that the TGFβ signaling pathway plays in leukemogenesis of BCP-ALL as well as in secondary drug resistance to dasatinib.
多激酶抑制剂达沙替尼已被证实对表达E2A-PBX1融合癌蛋白的前B细胞受体阳性急性淋巴细胞白血病具有疗效。TGFβ信号通路广泛参与胚胎发育、细胞稳态等多种细胞过程，在癌症发展中具有双重作用：早期抑制肿瘤生长，晚期介导肿瘤进展。本研究通过全转录组分析发现，在我们先前构建的人源达沙替尼耐药性pre-BCR+/E2A-PBX1+ ALL细胞中，TGFβ信号通路表达上调。我们证实耐药细胞中TGFβ通路成员SMAD3在转录和翻译水平均呈现上调。达沙替尼能在多个B细胞前体ALL细胞系及耐药性pre-BCR+/E2A-PBX1+ ALL细胞中，至少部分阻断TGFβ诱导的SMAD3磷酸化。在pre-BCR+/E2A-PBX1+ ALL细胞中，TGF-β1激活TGFβ信号通路可通过G0/G1期细胞周期阻滞、凋亡增加以及SMAD靶基因（如c-MYC下调）的转录改变来抑制细胞生长。这些结果深化了我们对TGFβ信号通路在B细胞前体ALL白血病发生及达沙替尼继发性耐药中作用机制的理解。
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