Figure 6.

Chromothriptic cure of WHIM patient WHIM-09. Chromothripsis, a Greek neologism that means chromosome shattering, affected one copy of chromosome 2 in a single hematopoietic stem cell from the patient. The WHIM copy of CXCR4 and 163 other genes on that chromosome were deleted and the remaining non-deleted shattered fragments were rejoined to form a derivative chromosome. The cell clonally expanded and selectively replaced the myeloid lineage with non-WHIM cells, resulting in clinical cure. The lymphoid lineage was unaffected by the event, so that the patient is a hematologic chimeric of WHIM lymphoid cells and chromothriptic non-WHIM myeloid cells. The patient is estimated to have lived >25 years since the chromothriptic event. This case report suggests that WHIM allele inactivation may be superior to WHIM allele correction as a gene therapy strategy. Consistent with this, Cxcr4 haploinsufficiency markedly enhanced hematopoietic reconstitution of donor HSCs and corrected leukopenia in unconditioned transplanted WHIM model mice. The figure is modified from Reference [58].