Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis.
Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis.
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DOI：
10.1007/s10875-017-0457-8
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发表时间：
2018-01
影响因子：
9.1
通讯作者：
Murphy PM
中科院分区：
文献类型：
--
作者：
Liu Q;Li Z;Y Yang A;Gao JL;S Velez D;J Cho E;McDermott DH;Murphy PM
WHIM-09 是第一例患有 WHIM 综合征的患者，这是一种与中性粒细胞骨髓潴留相关的常染色体显性中性粒细胞减少症形式。该患者最初被错误诊断为自身免疫性中性粒细胞减少症，9岁时接受了脾切除术，但中性粒细胞绝对计数（ANC）并未上升。随后，她因染色体碎裂（染色体破碎）而自然痊愈，这种疾病删除了单个造血干细胞 (HSC) 2 号染色体上的疾病等位基因 CXCR4R334X 和其他 163 个基因。染色质 CXCR4+/o HSC 取代了 CXCR4+/R334X WHIM HSC，ANC 升至新的持续良性基线，比正常值高出约 2-3 倍，但这一点仍无法解释。在这里，我们显示脾切除的 Cxcr4+/0 小鼠具有持续的良性中性粒细胞增多，在 WHIM-09 中表现出中性粒细胞增多的表型。此外，WHIM-09的粒细胞-巨噬细胞前体细胞具有增强的离体粒细胞集落形成活性。因此，WHIM-09的中性粒细胞增多可能是多因素的，涉及中性粒细胞外在因素（脾切除）以及CXCR4单倍体不足依赖性中性粒细胞内在因素（骨髓前体细胞分化增加）。 WHIM 突变赋予的中性粒细胞强烈的骨髓保留信号可能阻止了脾切除后的中性粒细胞增多，直到该突变被染色体碎裂删除。
WHIM-09 is the first patient described with WHIM syndrome, an autosomal dominant form of neutropenia related to bone marrow retention of neutrophils. Originally diagnosed incorrectly with autoimmune neutropenia, the patient underwent splenectomy at age 9, but the absolute neutrophil count (ANC) did not rise. Subsequently, she was spontaneously cured by chromothripsis (chromosome shattering), which deleted the disease allele CXCR4R334X, and 163 other genes, on chromosome 2 in a single hematopoietic stem cell (HSC). Chromothriptic CXCR4+/o HSCs replaced CXCR4+/R334X WHIM HSCs, and the ANC rose to a new sustained and benign baseline ~2–3-fold above normal that had remained unexplained. Here, we show that splenectomized Cxcr4+/0 mice had sustained and benign neutrophilia, phenocopying neutrophilia in WHIM-09. In addition, WHIM-09’s granulocyte-macrophage precursor cells possessed increased granulocyte colony-forming activity ex vivo. Thus, WHIM-09’s neutrophilia may be multifactorial, involving neutrophil-extrinsic factors (splenectomy), as well as CXCR4 haploinsufficiency-dependent neutrophil-intrinsic factors (increased myeloid precursor cell differentiation). The strong bone marrow retention signal for neutrophils conferred by the WHIM mutation may have prevented neutrophilia after splenectomy until the mutation was deleted by chromothripsis.
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影响因子：
5.4
作者：
Liu, Qian;Li, Zhanzhuo;Gao, Ji-Liang;Wan, Wuzhou;Ganesan, Sundar;McDermott, David H.;Murphy, Philip M.
通讯作者：
Murphy, Philip M.
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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作者：
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通讯作者：
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