Format

Send to

Choose Destination
Cell. 2015 Feb 12;160(4):686-699. doi: 10.1016/j.cell.2015.01.014. Epub 2015 Feb 5.

Chromothriptic cure of WHIM syndrome.

Author information

1
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2
Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
3
Quest Diagnostics, Chantilly, VA 20151, USA; Department of Cytogenetics, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
4
Quest Diagnostics, Chantilly, VA 20151, USA; Department of Human Genetics, Emory University School of Medicine, Decatur, GA 30030, USA.
5
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
6
Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
7
Clinical Services Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
8
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
9
Division of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
10
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Haematology, Tallaght Hospital, Dublin 24, Ireland.
11
INSERM UMR- S996, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, Université Paris-Sud, 92140 Clamart, France.
12
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pmm@nih.gov.

Abstract

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 repopulated 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 wild-type 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.

PMID:
25662009
PMCID:
PMC4329071
DOI:
10.1016/j.cell.2015.01.014
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center