Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis

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...

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Vydané v:	Journal of clinical immunology Ročník 38; číslo 1; s. 77 - 87
Hlavní autori:	Liu, Qian, Li, Zhanzhuo, Y. Yang, Alexander, Gao, Ji-Liang, S. Velez, Daniel, J. Cho, Elena, McDermott, David H., Murphy, Philip M.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Springer US 01.01.2018 Springer Nature B.V
Predmet:	Alleles Animals Benign Biomedical and Life Sciences Biomedicine Bone marrow Cell Differentiation - genetics Child Chromosome 2 Chromothripsis CXCR4 protein Disease Models, Animal Female Granulocytes Haploinsufficiency Hematopoietic stem cells Hematopoietic Stem Cells - physiology Humans Immunologic Deficiency Syndromes - diagnosis Immunologic Deficiency Syndromes - genetics Immunology Infectious Diseases Internal Medicine Leukocytes (granulocytic) Leukocytes (neutrophilic) Macrophages Medical Microbiology Mice Mice, Inbred C57BL Mice, Knockout Mutation Mutation - genetics Neutropenia Neutrophilia Neutrophils Neutrophils - physiology Original Article Primary Immunodeficiency Diseases Receptors, CXCR4 - genetics Splenectomy Stem cells Warts - diagnosis Warts - genetics mutation CXCR4 HSC WHIM syndrome Neutrophilia chromothripsis
ISSN:	0271-9142, 1573-2592, 1573-2592
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Shrnutí:	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 CXCR4 R334X , 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 +/o 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Case Study-2 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	0271-9142 1573-2592 1573-2592
DOI:	10.1007/s10875-017-0457-8