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Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis

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Abstract

WHIM-09 is the first patient described with WHIM syndrome, an autosomal dominant form of neutropenia related to bone marrow retention of neutrophils. Originally diagnosed incorrectly with autoimmune neutropenia, the patient underwent splenectomy at age 9, but the absolute neutrophil count (ANC) did not rise. Subsequently, she was spontaneously cured by chromothripsis (chromosome shattering), which deleted the disease allele CXCR4 R334X, and 163 other genes, on chromosome 2 in a single hematopoietic stem cell (HSC). Chromothriptic CXCR4 +/o HSCs replaced CXCR4 +/R334X WHIM HSCs, and the ANC rose to a new sustained and benign baseline ~ 2–3-fold above normal that had remained unexplained. Here, we show that splenectomized Cxcr4 +/o mice had sustained and benign neutrophilia, phenocopying neutrophilia in WHIM-09. In addition, WHIM-09’s granulocyte-macrophage precursor cells possessed increased granulocyte colony-forming activity ex vivo. Thus, WHIM-09’s neutrophilia may be multifactorial, involving neutrophil-extrinsic factors (splenectomy), as well as CXCR4 haploinsufficiency-dependent neutrophil-intrinsic factors (increased myeloid precursor cell differentiation). The strong bone marrow retention signal for neutrophils conferred by the WHIM mutation may have prevented neutrophilia after splenectomy until the mutation was deleted by chromothripsis.

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References

  1. Zuelzer WW. “Myelokathexis”—a new form of chronic granulocytopenia. Report of a case. N Engl J Med. 1964;270:699–704.

    Article  CAS  PubMed  Google Scholar 

  2. Wetzler M, Talpaz M, Kleinerman ES, King A, Huh YO, Gutterman JU, et al. A new familial immunodeficiency disorder characterized by severe neutropenia, a defective marrow release mechanism, and hypogammaglobulinemia. Am J Med. 1990;89(5):663–72.

    Article  CAS  PubMed  Google Scholar 

  3. Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet. 2003;34(1):70–4.

    Article  CAS  PubMed  Google Scholar 

  4. Walters KB, Green JM, Surfus JC, Yoo SK, Huttenlocher A. Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome. Blood. 2010;116(15):2803–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Aprikyan AA, Liles WC, Park JR, Jonas M, Chi EY, Dale DC. Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. Blood. 2000;95(1):320–7.

    CAS  PubMed  Google Scholar 

  6. Martin C, Burdon PC, Bridger G, Gutierrez-Ramos JC, Williams TJ, Rankin SM. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity. 2003;19(4):583–93.

    Article  CAS  PubMed  Google Scholar 

  7. Krill CE Jr, Smith HD, Mauer AM. Chronic idiopathic granulocytopenia. N Engl J Med. 1964;270:973–9.

    Article  PubMed  Google Scholar 

  8. McDermott DH, Gao JL, Liu Q, Siwicki M, Martens C, Jacobs P, et al. Chromothriptic cure of WHIM syndrome. Cell. 2015;160(4):686–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McDermott DH, Gao JL, Murphy PM. Chromothriptic cure of WHIM syndrome: implications for bone marrow transplantation. Rare Dis. 2015;3(1):e1073430.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Jones MJ, Jallepalli PV. Chromothripsis: chromosomes in crisis. Dev Cell. 2012;23(5):908–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. McBride JA, Dacie JV, Shapley R. The effect of splenectomy on the leucocyte count. Br J Haematol. 1968;14(2):225–31.

    Article  CAS  PubMed  Google Scholar 

  12. Tibblin E, Dreborg S, Erikson A, Hakansson G, Svennerholm L. Hematological findings in the Norrbottnian type of Gaucher disease. Eur J Pediatr. 1982;139(3):187–91.

    Article  CAS  PubMed  Google Scholar 

  13. McDermott DH, Liu Q, Velez D, Lopez L, Anaya-O’Brien S, Ulrick J, et al. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood. 2014;123(15):2308–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Devi S, Wang Y, Chew WK, Lima R, AG N, Mattar CN, et al. Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow. J Exp Med. 2013;210(11):2321–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Prystowsky MB, Otten G, Naujokas MF, Vardiman J, Ihle JN, Goldwasser E, et al. Multiple hemopoietic lineages are found after stimulation of mouse bone marrow precursor cells with interleukin 3. Am J Pathol. 1984;117(2):171–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Metcalf D, Johnson GR, Burgess AW. Direct stimulation by purified GM-CSF of the proliferation of multipotential and erythroid precursor cells. Blood. 1980;55(1):138–47.

    CAS  PubMed  Google Scholar 

  17. Lopez AF, To LB, Yang YC, Gamble JR, Shannon MF, Burns GF, et al. Stimulation of proliferation, differentiation, and function of human cells by primate interleukin 3. Proc Natl Acad Sci U S A. 1987;84(9):2761–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sawant KV, Poluri KM, Dutta AK, Sepuru KM, Troshkina A, Garofalo RP, et al. Chemokine CXCL1 mediated neutrophil recruitment: role of glycosaminoglycan interactions. Sci Rep. 2016;6:33123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Newburger PE. Disorders of neutrophil number and function. Hematol Am Soc Hematol Educ Program. 2006:104–10.

  20. Liu Q, Li Z, Gao JL, Wan W, Ganesan S, McDermott DH, et al. CXCR4 antagonist AMD3100 redistributes leukocytes from primary immune organs to secondary immune organs, lung, and blood in mice. Eur J Immunol. 2015;45(6):1855–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Doerschuk CM, Allard MF, Lee S, Brumwell ML, Hogg JC. Effect of epinephrine on neutrophil kinetics in rabbit lungs. J Appl Physiol (1985). 1988;65(1):401–7.

    Article  CAS  Google Scholar 

  22. Kreisel D, Nava RG, Li W, Zinselmeyer BH, Wang B, Lai J, et al. In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. Proc Natl Acad Sci U S A. 2010;107(42):18073–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Swamydas M, Lionakis MS. Isolation, purification and labeling of mouse bone marrow neutrophils for functional studies and adoptive transfer experiments. J Vis Exp. 2013;77:e50586.

    Google Scholar 

  24. Germing U, Kobbe G, Haas R, Gattermann N. Myelodysplastic syndromes: diagnosis, prognosis, and treatment. Dtsch Arztebl Int. 2013;110(46):783–90.

    PubMed  PubMed Central  Google Scholar 

  25. Eash KJ, Greenbaum AM, Gopalan PK, Link DC. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest. 2010;120(7):2423–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Richter R, Ruster B, Bistrian R, Forssmann WG, Seifried E, Henschler R. Beta-chemokine CCL15 affects the adhesion and migration of hematopoietic progenitor cells. Transfus Med Hemother. 2015;42(1):29–37.

    Article  PubMed  Google Scholar 

  27. Dale DC, Bolyard AA, Kelley ML, Westrup EC, Makaryan V, Aprikyan A, et al. The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. Blood. 2011;118(18):4963–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Psatha N, Sgouramali E, Gkountis A, Siametis A, Baliakas P, Constantinou V, et al. Superior long-term repopulating capacity of G-CSF+plerixafor-mobilized blood: implications for stem cell gene therapy by studies in the Hbb(th-3) mouse model. Hum Gene Ther Methods. 2014;25(6):317–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hayakawa J, Migita M, Ueda T, Fukazawa R, Adachi K, Ooue Y, et al. Dextran sulfate and stromal cell derived factor-1 promote CXCR4 expression and improve bone marrow homing efficiency of infused hematopoietic stem cells. J Nippon Med Sch. 2009;76(4):198–208.

    Article  CAS  PubMed  Google Scholar 

  30. Hernandez-Lopez C, Valencia J, Hidalgo L, Martinez VG, Zapata AG, Sacedon R, et al. CXCL12/CXCR4 signaling promotes human thymic dendritic cell survival regulating the Bcl-2/Bax ratio. Immunol Lett. 2008;120(1–2):72–8.

    Article  CAS  PubMed  Google Scholar 

  31. Weimar V. Macrocytic anemia and leucocytosis of guinea pigs with muscular stiffness disease. Proc Soc Exp Biol Med. 1954;85(3):488–91.

    Article  CAS  PubMed  Google Scholar 

  32. Gans RO, Stehouwer CD. Clinical thinking and decision-making in the practice. A patient with thrombophlebitis. Ned Tijdschr Geneeskd. 1999;143(46):2307–12.

    CAS  PubMed  Google Scholar 

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Funding

This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases.

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Authors and Affiliations

  1. Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg 10, Room 11N113, NIH, Bethesda, MD, 20892, USA

    Qian Liu, Zhanzhuo Li, Alexander Y. Yang, Ji-Liang Gao, Daniel S. Velez, Elena J. Cho, David H. McDermott & Philip M. Murphy

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  1. Qian Liu
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  2. Zhanzhuo Li
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  3. Alexander Y. Yang
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  4. Ji-Liang Gao
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  5. Daniel S. Velez
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  6. Elena J. Cho
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  7. David H. McDermott
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  8. Philip M. Murphy
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Contributions

Q.L., Z.L., and A.Y. generated and analyzed the experimental data; E.C., D.V., D.H.M., and P.M.M. provided patient recruitment and care; Q.L., D.H.M., and P.M.M. supervised the experiments and analyzed the data; J.L. provided mouse strains; and Q.L. and P.M.M. wrote the manuscript with participation from all of the other authors.

Corresponding author

Correspondence to Philip M. Murphy.

Ethics declarations

Consistent with the Declaration of Helsinki, all human subjects signed informed consent to participate in NIAID Institutional Review Board-approved clinical protocols at the NIH Clinical Center. All studies were reviewed and approved by the Animal Care and Use Committee of the NIAID, NIH. Human subjects research in this study was governed by a clinical research protocol approved by the Institutional Review Board of the National Institute of Allergy and Infectious Diseases, and written informed consent was obtained from all participants with WHIM syndrome prior to inclusion in the study. Mouse studies were governed by an Animal Study Protocol approved by the Animal Care and Use Committee of the National Institute of Allergy and Infectious Diseases.

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic Supplementary Material

Supplementary Figure 1

Mimicking WHIM-09 by splenectomy in Cxcr4+/o mice phenocopies neutrophilia. Cxcr4 +/+ and Cxcr4 +/o mice received splenectomy or sham surgery at 8 weeks of age, as indicated by the code at the top of each panel, and were bled at the indicated time points for 12.5 months post-operatively for determination of absolute neutrophil count (ANC). Data are the mean ± SD of results from one experiment conducted in the same manner as the experiment shown in Figure 1. The number of animals in each group was as follows: sham-operated Cxcr4 +/+, 3; splenectomized Cxcr4 +/+, 4; sham-operated Cxcr4 +/o, 3; splenectomized Cxcr4 +/o, 5. *p < 0.05, **p < 0.01,***p < 0.005, two-tailed unpaired parametric t test. (JPG 79.7 kb)

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Liu, Q., Li, Z., Y. Yang, A. et al. Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis. J Clin Immunol 38, 77–87 (2018). https://doi.org/10.1007/s10875-017-0457-8

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  • DOI: https://doi.org/10.1007/s10875-017-0457-8

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