F. Gaudin, M. Bachelerie, A. Espéli, and K. Dalloul, Balabanian are members of the LabEx LER MIT supported by ANR grant ANR-10-LABX-33 under the program Investissements d'Avenir ANR-11-IDEX-0003-01 This study was supported bythe Fondation de France (grant 2013 00038290) to F. Louache. C. Freitas was supported by DIM Biotherapies and the Sociéte Française d'Hématologie. J. Nguyen was a PhD fellow from the DIM Cancéropôle. V. Rondeau was supported by the Fondation pour la Recherche Médicale (FRM, grant ECO20160736102). V. Biajoux was supported by fellowships from the French Ministry for Education and the FRM. The authors declare no competing financial interests. Author contributions: C. Freitas designed and performed most of the experiments and contributed to manuscript writing, and V. Biajoux performed some of the experiments, analyzed data, and reviewed the manuscript ; M.-L. Aknin and F. Gaudin performed some of the experiments and analyzed data; S. Beaussant-Cohen, Y. Bertrand, and J. Donadieu provided blood samples from healthy and patients with WS and reviewed the manuscript; C. Bellanné-Chantelot performed the genetic analyses and reviewed the manuscript; F. Bachelerie and M

K. Balabanian, B. Lagane, J. L. Pablos, L. Laurent, T. Planchenault et al., WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12, Blood, vol.105, issue.6, pp.2449-2457, 2004.
DOI : 10.1182/blood-2004-06-2289

URL : https://hal.archives-ouvertes.fr/pasteur-00166808

K. Balabanian, A. Levoye, L. Klemm, B. Lagane, O. Hermine et al., Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling, Journal of Clinical Investigation, vol.118, pp.1074-1084, 2008.
DOI : 10.1172/JCI33187

URL : https://hal.archives-ouvertes.fr/pasteur-00285808

K. Balabanian, E. Brotin, V. Biajoux, L. Bouchet-delbos, E. Lainey et al., Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice, Blood, vol.119, issue.24, pp.5722-5730, 2012.
DOI : 10.1182/blood-2012-01-403378

M. T. Baldridge, K. Y. King, N. C. Boles, D. C. Weksberg, and M. A. , Quiescent haematopoietic stem cells are activated by IFN-?? in response to chronic infection, Nature, vol.111, issue.7299, pp.793-797, 2010.
DOI : 10.1038/nature09135

S. Beaussant-cohen, O. Fenneteau, E. Plouvier, P. Rohrlich, G. Daltroff et al., Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry, Orphanet Journal of Rare Diseases, vol.7, issue.1, 2012.
DOI : 10.1097/01.qai.0000137371.80695.ef

URL : https://hal.archives-ouvertes.fr/inserm-00796145

V. Biajoux, J. Natt, C. Freitas, N. Alouche, A. Sacquin et al., Efficient Plasma Cell Differentiation and Trafficking Require Cxcr4 Desensitization, Cell Reports, vol.17, issue.1, pp.193-205, 2016.
DOI : 10.1016/j.celrep.2016.08.068

URL : https://hal.archives-ouvertes.fr/inserm-01401695

H. E. Broxmeyer, C. M. Orschell, D. W. Clapp, G. Hangoc, S. Cooper et al., Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist, The Journal of Experimental Medicine, vol.126, issue.8, pp.1307-1318, 2005.
DOI : 10.1182/blood.V99.5.1585

S. K. Cho, T. D. Webber, J. R. Carlyle, T. Nakano, S. M. Lewis et al., Functional characterization of B lymphocytes generated in vitro from embryonic stem cells, Proc. Natl. Acad. Sci. USA, pp.9797-9802, 1999.
DOI : 10.1126/science.282.5391.1145

M. J. Christopher, F. Liu, M. J. Hilton, F. Long, and D. C. Link, Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization, Blood, vol.114, issue.7, pp.1331-1339, 2008.
DOI : 10.1182/blood-2008-10-184754

C. Gomes, A. , T. Hara, V. Y. Lim, D. Herndler-brandstetter et al., Hematopoietic Stem Cell Niches Produce Lineage-Instructive Signals to Control Multipotent Progenitor Differentiation, Immunity, vol.45, issue.6, pp.1219-1231, 2016.
DOI : 10.1016/j.immuni.2016.11.004

L. Ding and S. J. Morrison, Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches, Nature, vol.495, issue.7440, pp.231-235, 2013.
DOI : 10.1182/blood-2004-01-0272

URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600153

L. Dotta, L. Tassone, and R. Badolato, Clinical and Genetic Features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome, Current Molecular Medicine, vol.11, issue.4, pp.317-325, 2011.
DOI : 10.2174/156652411795677963

S. Doulatov, F. Notta, E. Laurenti, and J. E. Dick, Hematopoiesis: A Human Perspective, Cell Stem Cell, vol.10, issue.2, pp.120-136, 2012.
DOI : 10.1016/j.stem.2012.01.006

URL : http://doi.org/10.1016/j.stem.2012.01.006

K. J. Eash, A. M. Greenbaum, P. K. Gopalan, and D. C. Link, CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow, Journal of Clinical Investigation, vol.120, issue.7, pp.2423-2431, 2010.
DOI : 10.1172/JCI41649DS1

URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898597

A. Foudi, P. Jarrier, Y. Zhang, M. Wittner, J. Geay et al., Reduced retention of radioprotective hematopoietic cells within the bone marrow microenvironment in CXCR4-/- chimeric mice, Blood, vol.107, issue.6, pp.2243-2251, 2006.
DOI : 10.1182/blood-2005-02-0581

A. Galloway, A. Saveliev, S. ?ukasiak, D. J. Hodson, D. Bolland et al., RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence, Science, vol.21, issue.53, pp.453-459, 2016.
DOI : 10.1038/sj.onc.1206000

L. Gautreau, A. Boudil, V. Pasqualetto, L. Skhiri, L. Grandin et al., Gene Coexpression Analysis in Single Cells Indicates Lymphomyeloid Copriming in Short-Term Hematopoietic Stem Cells and Multipotent Progenitors, The Journal of Immunology, vol.184, issue.9, pp.4907-4917, 2010.
DOI : 10.4049/jimmunol.0902184

A. V. Gulino, D. Moratto, S. Sozzani, P. Cavadini, K. Otero et al., Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, Blood, vol.104, issue.2, pp.444-452, 2004.
DOI : 10.1182/blood-2003-10-3532

P. A. Hernandez, R. J. Gorlin, J. N. Lukens, S. Taniuchi, J. Bohinjec et al., Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease, Nature Genetics, vol.34, issue.1, pp.70-74, 2003.
DOI : 10.1038/ng1149

I. Hidalgo, A. Herrera-merchan, J. M. Ligos, L. Carramolino, J. Nuñez et al., Ezh1 Is Required for Hematopoietic Stem Cell Maintenance and Prevents Senescence-like Cell Cycle Arrest, Cell Stem Cell, vol.11, issue.5, pp.649-662, 2012.
DOI : 10.1016/j.stem.2012.08.001

URL : http://doi.org/10.1016/j.stem.2012.08.001

C. N. Inra, B. O. Zhou, M. Acar, M. M. Murphy, J. Richardson et al., A perisinusoidal niche for extramedullary haematopoiesis in the spleen, Nature, vol.47, issue.7579, pp.466-471, 2015.
DOI : 10.1038/nature15530

T. Itkin, S. Gur-cohen, J. A. Spencer, A. Schajnovitz, S. K. Ramasamy et al., Distinct bone marrow blood vessels differentially regulate haematopoiesis, Nature, vol.124, issue.7599, pp.323-328, 2016.
DOI : 10.1038/nature17624

K. Ito, A. Hirao, F. Arai, K. Takubo, S. Matsuoka et al., Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells, Nature Medicine, vol.168, issue.4, pp.446-451, 2006.
DOI : 10.1172/JCI200422475

D. Karpova and H. Bonig, Concise Review: CXCR4/CXCL12 Signaling in Immature Hematopoiesis-Lessons From Pharmacological and Genetic Models, STEM CELLS, vol.49, issue.8, pp.2391-2399, 2015.
DOI : 10.1002/stem.2054

K. Kawabata, M. Ujikawa, T. Egawa, H. Kawamoto, K. Tachibana et al., A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution, Proc. Natl. Acad. Sci. USA, pp.5663-5667, 1999.
DOI : 10.1038/nm0198-072

T. Kawai and H. L. Malech, WHIM syndrome: congenital immune deficiency disease, Current Opinion in Hematology, vol.16, issue.1, pp.20-26, 2009.
DOI : 10.1097/MOH.0b013e32831ac557

URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673024

T. Kawai, U. Choi, L. Cardwell, S. S. Deravin, N. Naumann et al., WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus-truncated CXCR4, Blood, vol.109, issue.1, pp.78-84, 2007.
DOI : 10.1182/blood-2006-05-025296

K. Kozar, M. A. Ciemerych, V. I. Rebel, H. Shigematsu, A. Zagozdzon et al., Mouse Development and Cell Proliferation in the Absence of D-Cyclins, Cell, vol.118, issue.4, pp.477-491, 2004.
DOI : 10.1016/j.cell.2004.07.025

G. Kriván, M. Erdos, K. Kállay, G. Benyó, A. Tóth et al., Successful umbilical cord blood stem cell transplantation in a child with WHIM syndrome, European Journal of Haematology, vol.81, issue.3, pp.274-275, 2010.
DOI : 10.1111/j.1600-0609.2009.01368.x

C. Lai, S. Yamazaki, M. Okabe, S. Suzuki, Y. Maeyama et al., Stage-Specific Roles for Cxcr4 Signaling in Murine Hematopoietic Stem/Progenitor Cells in the Process of Bone Marrow Repopulation, STEM CELLS, vol.106, issue.7, pp.1929-1942, 2014.
DOI : 10.1002/stem.1670

Q. Ma, D. Jones, P. R. Borghesani, R. A. Segal, T. Nagasawa et al., Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice, Proc. Natl. Acad. Sci. USA, pp.9448-9453, 1998.
DOI : 10.1038/31269

URL : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC21358/pdf

D. H. Mcdermott, J. Gao, Q. Liu, M. Siwicki, C. Martens et al., Chromothriptic Cure of WHIM Syndrome, Cell, vol.160, issue.4, pp.686-699, 2015.
DOI : 10.1016/j.cell.2015.01.014

Y. Miwa, T. Hayashi, S. Suzuki, S. Abe, I. Onishi et al., Up-regulated expression of CXCL12 in human spleens with extramedullary haematopoiesis, Pathology, vol.45, issue.4, pp.408-416, 2013.
DOI : 10.1097/PAT.0b013e3283613dbf

S. J. Morrison, D. E. Wright, and I. L. Weissman, Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization, Proc. Natl. Acad. Sci. USA, 1908.
DOI : 10.1038/nm0296-198

URL : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20016/pdf

T. Nagasawa, S. Hirota, K. Tachibana, N. Takakura, S. Nishikawa et al., Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1, Nature, vol.382, issue.6592, pp.635-638, 1996.
DOI : 10.1038/382635a0

T. Nagasawa, K. Tachibana, and T. Kishimoto, A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection, Seminars in Immunology, vol.10, issue.3, pp.179-1850128, 1998.
DOI : 10.1006/smim.1998.0128

Y. Nie, Y. Han, and Y. Zou, CXCR4 is required for the quiescence of primitive hematopoietic cells, The Journal of Experimental Medicine, vol.18, issue.4, pp.777-783, 2008.
DOI : 10.1016/j.stem.2007.07.010

N. Onai, . Yy, H. Zhang, T. Yoneyama, S. Kitamura et al., Impairment of lymphopoiesis and myelopoiesis in mice reconstituted with bone marrow-hematopoietic progenitor cells expressing SDF-1-intrakine, Blood, vol.96, pp.2074-2080, 2000.

K. W. Orford and D. T. Scadden, Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation, Nature Reviews Genetics, vol.13, issue.2, pp.115-128, 2008.
DOI : 10.1038/nrg2269

A. Peled, I. Petit, O. Kollet, M. Magid, T. Ponomaryov et al., Dependence of human stem cell engraftment and repopulation of NOD, 1999.

L. A. Pitt, A. N. Tikhonova, H. Hu, T. Trimarchi, B. King et al., CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance, Cancer Cell, vol.27, issue.6, pp.755-768, 2015.
DOI : 10.1016/j.ccell.2015.05.002

URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461838

M. L. Scimone, T. W. Felbinger, I. B. Mazo, J. V. Stein, U. H. Von-andrian et al., CXCL12 Mediates CCR7-independent Homing of Central Memory Cells, But Not Naive T Cells, in Peripheral Lymph Nodes, The Journal of Experimental Medicine, vol.132, issue.8, pp.1113-1120, 2004.
DOI : 10.1016/S0092-8674(02)01139-X

L. Shao, H. Li, S. K. Pazhanisamy, A. Meng, Y. Wang et al., Reactive oxygen species and hematopoietic stem cell senescence, International Journal of Hematology, vol.7, issue.1, pp.24-32, 2011.
DOI : 10.1007/s12185-011-0872-1

URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390185

T. Sugiyama, H. Kohara, M. Noda, and T. Nagasawa, Maintenance of the Hematopoietic Stem Cell Pool by CXCL12-CXCR4 Chemokine Signaling in Bone Marrow Stromal Cell Niches, Immunity, vol.25, issue.6, pp.977-988, 2006.
DOI : 10.1016/j.immuni.2006.10.016

P. C. Trampont, A. Tosello-trampont, Y. Shen, A. K. Duley, A. E. Sutherland et al., CXCR4 acts as a costimulator during thymic ??-selection, Nature Immunology, vol.170, issue.2, pp.162-170, 2010.
DOI : 10.1016/j.cell.2008.06.036

URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808461

J. J. Tsai, J. A. Dudakov, K. Takahashi, J. Shieh, E. Velardi et al., Nrf2 regulates haematopoietic stem cell function, Nrf2 regulates haematopoietic stem cell function, pp.309-316, 2013.
DOI : 10.1038/ncb2699

URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699879

Y. Tzeng, H. Li, Y. Kang, W. Chen, W. Cheng et al., Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression, Blood, vol.117, issue.2, pp.429-439, 2011.
DOI : 10.1182/blood-2010-01-266833

X. Wang, S. Y. Cho, C. S. Hu, D. Chen, J. Roboz et al., C-X-C motif chemokine 12 influences the development of extramedullary hematopoiesis in the spleens of myelofibrosis patients, Experimental Hematology, vol.43, issue.2, pp.100-109, 2015.
DOI : 10.1016/j.exphem.2014.10.013

A. Wilson, E. Laurenti, G. Oser, R. C. Van-der-wath, W. Blanco-bose et al., Hematopoietic Stem Cells Reversibly Switch from Dormancy to Self-Renewal during Homeostasis and Repair, Cell, vol.135, issue.6, pp.1118-1129, 2008.
DOI : 10.1016/j.cell.2008.10.048

URL : http://doi.org/10.1016/j.cell.2009.06.020

B. C. Wolf and R. S. Neiman, Hypothesis: splenic filtration and the pathogenesis of extramedullary hematopoiesis in agnogenic myeloid metaplasia, Hematol. Pathol, vol.1, pp.77-80, 1987.

T. Yahata, T. Takanashi, Y. Muguruma, A. A. Ibrahim, H. Matsuzawa et al., Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells, Blood, vol.118, issue.11, pp.2941-2950, 2011.
DOI : 10.1182/blood-2011-01-330050

K. Young, S. Borikar, R. Bell, L. Kuffler, V. Philip et al., Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging, The Journal of Experimental Medicine, vol.213, issue.11, pp.2259-2267, 2016.
DOI : 10.1038/cmi.2015.39

Y. Zhang, A. Foudi, J. Geay, M. Berthebaud, D. Buet et al., Hematopoietic Progenitor Cells, Stem Cells, vol.276, issue.6, pp.1015-102922, 2004.
DOI : 10.1634/stemcells.22-6-1015

Y. Zhang, M. Dépond, L. He, A. Foudi, E. O. Kwarteng et al., CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress, Scientific Reports, vol.996, issue.1, p.37827, 2016.
DOI : 10.1111/j.1749-6632.2003.tb03237.x

URL : https://hal.archives-ouvertes.fr/inserm-01472381