On the mechanism of leukocytosis in patient WHIM-09, cured of WHIM syndrome by chromothripsis

• Published in: The Journal of immunology (1950) 2017-05, Vol.198 (1_Supplement), p.60-60.20
• Main Authors: Liu, Qian, Li, Zhanzhuo, Yang, Alexander, Velez, Daniel, Stregevsky, Elina, Cho, Elena, Holmes, Kevin, McDermott, David H., Murphy, Philip M.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.198.Supp.60.20

Patient WHIM-09 was cured of WHIM syndrome, an autosomal dominant immunodeficiency disorder caused by gain-of-function CXCR4 mutations, by chromothripsis (chromosome shattering) in a single hematopoietic stem cell (HSC). Chromothripsis fortuitously deleted CXCR4WHIM, and one copy of 163 other genes, resulting in hematopoietic chimerism (100% chromothriptic myeloid cells and 100% WHIM lymphoid cells) and overcorrection of leukopenia in neutrophil and monocyte, but not lymphocyte, lineages to levels stably ~2-fold above normal. Earlier, splenectomy had increased the absolute lymphocyte count stably by ~2-fold. To address leukocytosis mechanisms, we analyzed animal models and patient samples. The total WBC count was increased by splenectomy in wild-type mice, and by Cxcr4 haploinsufficiency in sham or splenectomized mice, due to increases in lymphocytes and monocytes, not neutrophils. Cxcr4 haploinsufficiency also increased mouse bone marrow LSK cell proliferation and reduced neutrophil homing from blood to bone marrow. In the patient, the frequency, absolute number and myeloid colony-forming capacity of blood CD34+ cells were normal; however, bone marrow GMPs generated increased G/M/GM-CFU colonies in vitro. WHIM-09 serum contained increased levels of Groa, MIP-1d, MIG, IL-8 and IL-15, and decreased levels of CXCR4’s ligand SDF-1, which may regulate leukocyte levels. Thus, in WHIM-09 splenectomy and CXCR4 haploinsufficiency may have contributed to monocytosis; whereas HSC hyperproliferation, enhanced differentiation capacity of GMPs, impaired neutrophil homing to bone marrow and skewed serum cytokine levels may all contribute to aspects of leukocytosis.