促转移酪氨酸磷酸酶 PRL-3（PTP4A3）是 BCR-ABL 在人类慢性髓性白血病中致癌功能的新型介质。

BACKGROUND

Resistance to tyrosine kinase inhibitors (TKIs) remains a challenge in management of patients with chronic myeloid leukemia (CML). A better understanding of the BCR-ABL signalling network may lead to better therapy.

FINDINGS

Here we report the discovery of a novel downstream target of BCR-ABL signalling, PRL-3 (PTP4A3), an oncogenic tyrosine phosphatase. Analysis of CML cancer cell lines and CML patient samples reveals the upregulation of PRL-3. Inhibition of BCR-ABL signalling either by Imatinib or by RNAi silencing BCR-ABL reduces PRL-3 and increases cleavage of PARP. In contrast, the amount of PRL-3 protein remains constant or even increased in response to Imatinib treatment in drug resistant cells expressing P210 T315I. Finally, analysis with specific shRNA shows PRL-3 involvement in the proliferation and self-renewal of CML cells.

CONCLUSIONS

These data support a role for PRL-3 in BCR-ABL signalling and CML biology and may be a potential therapeutic target downstream of BCR-ABL in TKI resistant mutant cells.

背景

酪氨酸激酶抑制剂（TKIs）耐药仍然是慢性髓系白血病（CML）患者治疗的一个挑战。更好地了解 BCR-ABL 信号网络可能会带来更好的治疗方法。

结果

我们在这里报告了 BCR-ABL 信号下游的一个新的靶标 PRL-3（PTP4A3）的发现，PRL-3 是一种致癌性的酪氨酸磷酸酶。对 CML 癌细胞系和 CML 患者样本的分析显示 PRL-3 的上调。BCR-ABL 信号的抑制，无论是通过伊马替尼还是通过 RNAi 沉默 BCR-ABL，都降低了 PRL-3 的水平，并增加了 PARP 的切割。相比之下，在表达 P210 T315I 的耐药细胞中，伊马替尼治疗后 PRL-3 蛋白的量保持不变甚至增加。最后，用特异性 shRNA 的分析表明 PRL-3 参与了 CML 细胞的增殖和自我更新。