title: Chromothriptic cure of WHIM syndrome.
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.
authors: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: David H
authors: DH
authors: McDermott
authors: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Ji-Liang
authors: JL
authors: Gao
authors: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Qian
authors: Q
authors: Liu
authors: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Marie
authors: M
authors: Siwicki
authors: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
authors: Craig
authors: C
authors: Martens
authors: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Paejonette
authors: P
authors: Jacobs
authors: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Daniel
authors: D
authors: Velez
authors: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Erin
authors: E
authors: Yim
authors: Quest Diagnostics, Chantilly, VA 20151, USA; Department of Cytogenetics, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Christine R
authors: CR
authors: Bryke
authors: Quest Diagnostics, Chantilly, VA 20151, USA; Department of Cytogenetics, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Nancy
authors: N
authors: Hsu
authors: Quest Diagnostics, Chantilly, VA 20151, USA; Department of Human Genetics, Emory University School of Medicine, Decatur, GA 30030, USA.
authors: Zunyan
authors: Z
authors: Dai
authors: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Martha M
authors: MM
authors: Marquesen
authors: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Elina
authors: E
authors: Stregevsky
authors: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Nana
authors: N
authors: Kwatemaa
authors: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Narda
authors: N
authors: Theobald
authors: Clinical Services Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
authors: Debra A
authors: DA
authors: Long Priel
authors: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Stefania
authors: S
authors: Pittaluga
authors: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Mark A
authors: MA
authors: Raffeld
authors: Division of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Katherine R
authors: KR
authors: Calvo
authors: Division of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Irina
authors: I
authors: Maric
authors: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Haematology, Tallaght Hospital, Dublin 24, Ireland.
authors: Ronan
authors: R
authors: Desmond
authors: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Kevin L
authors: KL
authors: Holmes
authors: Clinical Services Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
authors: Douglas B
authors: DB
authors: Kuhns
authors: INSERM UMR- S996, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, Université Paris-Sud, 92140 Clamart, France.
authors: Karl
authors: K
authors: Balabanian
authors: INSERM UMR- S996, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, Université Paris-Sud, 92140 Clamart, France.
authors: Françoise
authors: F
authors: Bachelerie
authors: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
authors: Stephen F
authors: SF
authors: Porcella
authors: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Harry L
authors: HL
authors: Malech
authors: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pmm@nih.gov.
authors: Philip M
authors: PM
authors: Murphy
mesh_terms: D000818:Animals; D043171:Chromosomal Instability; D002877:Chromosomes, Human; D004195:Disease Models, Animal; D057895:Haploinsufficiency; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009030:Mosaicism; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism; D000081207:Primary Immunodeficiency Diseases; D019718:Receptors, CXCR4 / Q000235:genetics; D012075:Remission, Spontaneous; D014860:Warts / Q000235:genetics*
chemical_list: C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D019718:Receptors, CXCR4