Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin
Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin
复制标题
脯氨酰 4-羟化酶 2 通过 Carabin 羟基化促进 B 细胞淋巴瘤进展
DOI：
10.1182/blood-2017-07-794875
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发表时间：
2018-03-22
期刊：
影响因子：
20.3
通讯作者：
Dang, Yongjun
中科院分区：
文献类型：
--
作者：
Jiang, Wei;Zhou, Xiaoyan;Dang, Yongjun
B细胞淋巴瘤是具有有限治疗选择的异质性血液疾病，主要是因为它们易于复发并且变得难以治疗。Carabin是B细胞受体信号传导和增殖的关键抑制剂，在B细胞淋巴瘤中通过未知机制失活。在这里，我们确定脯氨酰4-羟化酶2（P4 HA 2）作为一个特定的脯氨酸羟化酶的Carabin。Carabin羟基化导致其蛋白酶体降解，从而激活Ras/细胞外信号调节激酶途径并增加B细胞淋巴瘤增殖。P4 HA 2在正常B细胞中检测不到，但在弥漫性大B细胞淋巴瘤（DLBCL）中上调，驱动Carabin失活和淋巴瘤增殖。我们的研究结果表明，P4 HA 2是DLBCL的一个潜在的预后标志物和一个有前途的药理学目标，为发展治疗的分子分层B细胞淋巴瘤。
B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of their propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B-cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms. Here, we identify prolyl 4-hydroxylase 2 (P4HA2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/extracellular signal-regulated kinase pathway and increasing B-cell lymphoma proliferation. P4HA2 is undetectable in normal B cells but upregulated in the diffuse large B-cell lymphoma (DLBCL), driving Carabin inactivation and lymphoma proliferation. Our results indicate that P4HA2 is a potential prognosis marker for DLBCL and a promising pharmacological target for developing treatment of molecularly stratified B-cell lymphomas.