Chromothriptic Cure of WHIM Syndrome
Chromothriptic Cure of WHIM Syndrome
复制标题
DOI：
10.1016/j.cell.2015.01.014
复制
发表时间：
2015-02-12
期刊：
影响因子：
64.5
通讯作者：
Murphy, Philip M.
中科院分区：
文献类型：
--
作者：
McDermott, David H.;Gao, Ji-Liang;Murphy, Philip M.
染色体碎裂是最近描述的癌症中的灾难性细胞事件，其中染色体经历大规模缺失和重排。在这里，我们报告的情况下，chromothripsis自发治愈WHIM综合征，一种常染色体显性联合免疫缺陷病的趋化因子受体CXCR4的功能获得性突变引起的患者。在该患者中，疾病等位基因CXCR4（R334X）以及来自2号染色体的一个拷贝的163个其他基因的缺失发生在造血干细胞（HSC）中，造血干细胞（HSC）重新填充髓系而不是淋巴系。在竞争性小鼠骨髓（BM）移植实验中，Cxcr 4单倍不足足以赋予供体BM较野生型或WHIM综合征模型小鼠BM强的长期植入优势，表明患者治愈的潜在机制。我们的研究结果表明，CXCR4的部分失活可能具有普遍的效用，作为一种策略，以促进造血干细胞移植植入。
Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that re-populated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wildtype or WHIM syndrome model mice, suggesting a potential mechanism for the patient's cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation.