Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization

Christelle Freitas; Monika Wittner; Julie Nguyen; Vincent Rondeau; Vincent Biajoux; Marie-Laure Aknin; Françoise Gaudin; Sarah Beaussant-Cohen; Yves Bertrand; Christine Bellanné-Chantelot; Jean Donadieu; Françoise Bachelerie; Marion Espéli; Ali Dalloul; Fawzia Louache; Karl Balabanian

doi:10.1084/jem.20160806

Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization

Christelle Freitas ¹ Monika Wittner ² Julie Nguyen ¹ Vincent Rondeau ¹ Vincent Biajoux ³ Marie-Laure Aknin ⁴ Françoise Gaudin ^{4, 1} Sarah Beaussant-Cohen ⁵ Yves Bertrand ⁶ Christine Bellanné-Chantelot ⁷ Jean Donadieu ^{8, 9, 10} Françoise Bachelerie ¹ Marion Espéli ¹ Ali Dalloul ¹ Fawzia Louache ² Karl Balabanian ^{1, *}

* Auteur correspondant

1 Inflammation, chimiokines et immunopathologie

2 U1170 Inserm - Hématopoïèse normale et pathologique

3 Cytokines, chimiokines et immunopathologie

4 Institut Paris-Saclay d’Innovation Thérapeutique (IPSIT)

5 Service d’Hémato-Oncologie Pédiatrique

6 Service d’Hémato-Oncologie Pédiatrique

7 Département de Génétique

8 Registre français des neutropénies chroniques sévères

9 Centre de référence des déficits Immunitaires Héréditaires

10 Service d'hématologie-immunologie-oncologie pédiatrique

Abstract : The CXCL12/CXCR4 signaling exerts a dominant role in promoting HSPC retention and quiescence in BM. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome (WS), a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WS-linked gain-of-function Cxcr4 mutation, we explored the possibility that the lymphopenia in WS arises from defects at HSPC level. We reported that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term HSCs and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating HSPCs in five patients with WS. This was also evidenced in WS mice and mirrored by accumulation of HSPCs in the spleen, where we observed enhanced extramedullary hematopoiesis. Therefore, efficient Cxcr4 desensitization is critical for lymphoid differentiation of HSPCs and its impairment is a key mechanism underpinning the lymphopenia observed in mice and likely in WS patients.

Type de document :

Article dans une revue

Journal of Experimental Medicine, Rockefeller University Press, 2017, Epub ahead of print. 〈10.1084/jem.20160806〉

Domaine :

Sciences du Vivant [q-bio] / Médecine humaine et pathologie / Hématologie

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http://www.hal.inserm.fr/inserm-01528648
Contributeur : Karl Balabanian <>
Soumis le : lundi 29 mai 2017 - 14:06:28
Dernière modification le : jeudi 11 octobre 2018 - 17:06:01

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Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization

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Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization

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