Cell
Volume 160, Issue 4, 12 February 2015, Pages 686-699
Journal home page for Cell

Article
Chromothriptic Cure of WHIM Syndrome

https://doi.org/10.1016/j.cell.2015.01.014Get rights and content
Under an Elsevier user license
open archive

Highlights

  • CXCR4 haploinsufficiency may promote HSC engraftment

  • Chromothriptic deletions result in functional cure of WHIM syndrome

  • Clinical symptoms in WHIM syndrome are dependent on myeloid deficits

  • Myeloid-derived cells are critical for control of HPV infection

Summary

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, CXCR4R334X, 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.

Cited by (0)

14

Co-first author