The WHIM-like CXCR4S338X somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia
The WHIM-like CXCR4S338X somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia
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DOI：
10.1038/leu.2014.187
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发表时间：
2015-01-01
期刊：
影响因子：
11.4
通讯作者：
Treon, S. P.
中科院分区：
文献类型：
--
作者：
Cao, Y.;Hunter, Z. R.;Treon, S. P.
CXCR4(Whim)体细胞突变是常见的Waldenstrom巨球蛋白血症(WM)，与临床对伊布鲁替尼的耐药性有关。我们改造了WM细胞来表达WM中最常见的突发事件(尖锐湿疣、低丙种球蛋白血症、感染和骨髓病变)，即CXCRS338X突变。与CXCR4野生型(WT)细胞相比，SDF-1a刺激后，CXCR4(S338X)WM细胞的受体内化降低，AKT和ERK信号增强和持续，聚(ADP-核糖)聚合酶和caspase3裂解减少，Annexin V染色减少。CXCR4(S338X)相关信号和存活效应可被CXCR4抑制剂AMD3100阻断。与CXCR4(WT)细胞相比，SDF-1a处理的CXCR4(S338X)WM细胞表现出持续的AKT和ERK激活，并减少了凋亡变化，AMD3100也逆转了这一发现。AKT或ERK拮抗剂可恢复SDF-1a诱导的CXCR4(S338X)WM细胞的凋亡改变，显示其在SDF-1a介导的ibrutinib耐药中的作用。CXCR4(WIM)与CXCR4(WT)WM患者相比，骨髓PACK染色增强也很明显，尽管CXCR4(WIM)患者接受伊布鲁替尼治疗，但PACT染色仍然活跃。最后，CXCR4(S338X)WM细胞在SDF-1a存在的情况下对其他西药相关治疗药物表现出不同程度的耐药，包括苯达莫司汀、氟达拉滨、硼替佐米和idelalisib。这些研究证实了CXCR4(Whim)突变的功能作用，并为研究CXCR4抑制剂在西医中的作用提供了一个框架。
CXCR4(WHIM) somatic mutations are common Waldenstrom's Macroglobulinemia (WM), and are associated with clinical resistance to ibrutinib. We engineered WM cells to express the most common WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis), CXCRS338X mutation in WM. Following SDF-1a stimulation, CXCR4(S338X) WM cells exhibited decreased receptor internalization, enhanced and sustained AKT kinase (AKT) and extracellular regulated kinase (ERK) signaling, decreased poly (ADP-ribose) polymerase and caspase 3 cleavage, and decreased Annexin V staining versus CXCR4 wild-type (WT) cells. CXCR4(S338X)-related signaling and survival effects were blocked by the CXCR4 inhibitor AMD3100. SDF-1a-treated CXCR4(S338X) WM cells showed sustained AKT and ERK activation and decreased apoptotic changes versus CXCR4(WT) cells following ibrutinib treatment, findings which were also reversed by AMD3100. AKT or ERK antagonists restored ibrutinib-triggered apoptotic changes in SDF-1a-treated CXCR4(S338X) WM cells demonstrating their role in SDF-1a-mediated ibrutinib resistance. Enhanced bone marrow pAKT staining was also evident in CXCR4(WHIM) versus CXCR4(WT) WM patients, and remained active despite ibrutinib therapy in CXCR4(WHIM) patients. Last, CXCR4(S338X) WM cells showed varying levels of resistance to other WM relevant therapeutics, including bendamustine, fludarabine, bortezomib and idelalisib in the presence of SDF-1a. These studies demonstrate a functional role for CXCR4(WHIM) mutations, and provide a framework for investigation of CXCR4 inhibitors in WM.