title: WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus-truncated CXCR4.
abstract: WHIM(warts, hypogammaglobulinemia, recurrent bacterial infection, and myelokathexis) syndrome is a rare immunodeficiency caused in many cases by autosomal dominant C-terminal truncation mutations in the 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 nonobese diabetic/severe combined immunodeficiency (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 a 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 bone marrow (BM) apoptosis or the release of transduced leukocytes into PB. However, mutated CXCR4 transgene expression further enhanced BM engraftment, but was associated with a 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.
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bldg 10-CRC 5-West Labs, Rm 5-3750, 10 Center Dr MSC 1456, Bethesda, MD 20892-1456, USA.
authors.forename: Toshinao
authors.initials: T
authors.lastname: Kawai
authors.forename: Uimook
authors.initials: U
authors.lastname: Choi
authors.forename: Lanise
authors.initials: L
authors.lastname: Cardwell
authors.forename: Suk See
authors.initials: SS
authors.lastname: DeRavin
authors.forename: Nora
authors.initials: N
authors.lastname: Naumann
authors.forename: Narda L
authors.initials: NL
authors.lastname: Whiting-Theobald
authors.forename: Gilda F
authors.initials: GF
authors.lastname: Linton
authors.forename: Jaehyun
authors.initials: J
authors.lastname: Moon
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
mesh_terms: D000361:Agammaglobulinemia / Q000235:genetics*; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D001424:Bacterial Infections / Q000209:etiology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D020013:Calcium Signaling; D002465:Cell Movement; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology; D003114:Colony-Forming Units Assay; D004198:Disease Susceptibility; D018628:Gene Dosage; D006085:Graft Survival; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020125:Mutation, Missense; D009503:Neutropenia / Q000235:genetics*; D036102:Peripheral Blood Stem Cell Transplantation; D017354:Point Mutation; D011828:Radiation Chimera; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012008:Recurrence; D019076:Transgenes; D014183:Transplantation, Heterologous; D014860:Warts / Q000235:genetics*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins