Submitted May 30, 2006
Accepted August 14, 2006
WHIM syndrome myelokathexis reproduced in the NOD/SCID
mouse xenotransplant model engrafted with healthy human
stem cells transduced with C-terminus truncated CXCR4
Toshinao Kawai, Uimook Choi, Lanise Cardwell, Suk See DeRavin, Nora Naumann, Narda L Whiting-Theobald, Gilda F Linton, Jaehyun Moon, Philip M Murphy, and Harry L Malech*
National Institute of Allergy and Infectious Diseases, NIH
* Corresponding author; email: hmalech{at}nih.gov.
WHIM syndrome is a rare immunodeficiency caused in many
cases by autosomal dominant C-terminal truncation
mutations in chemokine receptor CXCR4. A prominent and
unexplained feature of WHIM is myelokathexis
(hypercellularity with apoptosis of mature myeloid cells
in bone marrow and neutropenia). We transduced healthy
human CD34+ peripheral blood mobilized stem
cells (PBSCs) with retrovirus vector encoding wild type
(wt) CXCR4 or WHIM type mutated-CXCR4 and studied these
cells ex vivo in culture and after engraftment in a
NOD/SCID mouse xenograft model. Neither wt-CXCR4 nor
mutated-CXCR4 transgene expression itself enhanced
apoptosis of neutrophils arising in transduced PBSC
cultures even with stimulation by CXCR4 agonist, stromal
cell- derived factor-1 (SDF-1 [CXCL12]). Excess wt-CXCR4
expression by transduced human PBSCs enhanced marrow
engraftment, but did not affect BM apoptosis nor release
of transduced leukocytes into peripheral blood (PB).
However, mutated-CXCR4 transgene expression further
enhanced BM engraftment, but was associated with
significant increase in apoptosis of transduced cells in
BM and reduced release of transduced leukocytes into PB.
We conclude that increased apoptosis of mature myeloid
cells in WHIM is secondary to a failure of marrow release
and progression to normal myeloid cell senescence, and not
a direct effect of activation of mutated-CXCR4.