CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88L265P-directed survival signalling in Waldenstrom macroglobulinaemia cells
CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88L265P-directed survival signalling in Waldenstrom macroglobulinaemia cells
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DOI：
10.1111/bjh.13200
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发表时间：
2015-03-01
影响因子：
6.5
通讯作者：
Treon, Steven P.
中科院分区：
文献类型：
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作者：
Cao, Yang;Hunter, Zachary R.;Treon, Steven P.
CXCR 4（WHIM）移码和无义突变发生在MYD 88（L265 P）之后，是瓦尔登斯特伦巨球蛋白血症（WM）中最常见的体细胞变异，并影响临床表现和伊曲替尼应答。虽然已经研究了无义（CXCR 4（S338 X））突变，但对CXCR 4移码（CXCR 4（FS））突变知之甚少。我们设计WM细胞以表达患者中存在的CXCR 4（FS）突变，并将其CXCL 12（SDF-1a）诱导的信号传导和伊鲁替尼敏感性与CXCR 4（野生型（WT））和CXCR 4（S338 X）细胞进行比较。CXCL 12刺激后，CXCR 4（FS）和CXCR 4（S338 X）WM细胞表现出CXCR 4受体内化受损，AKT 1（也称为AKT）和MAPK 1（也称为ERK）活化增强（P
CXCR4(WHIM) frameshift and nonsense mutations follow MYD88(L265P) as the most common somatic variants in Waldenstrom Macroglobulinaemia (WM), and impact clinical presentation and ibrutinib response. While the nonsense (CXCR4(S338X)) mutation has been investigated, little is known about CXCR4 frameshift (CXCR4(FS)) mutations. We engineered WM cells to express CXCR4(FS) mutations present in patients, and compared their CXCL12 (SDF-1a) induced signalling and ibrutinib sensitivity to CXCR4(wild-type (WT)) and CXCR4(S338X) cells. Following CXCL12 stimulation, CXCR4(FS) and CXCR4(S338X) WM cells showed impaired CXCR4 receptor internalization, and enhanced AKT1 (also termed AKT) and MAPK1 (also termed ERK) activation versus CXCRWT cells (P