The HOXB4 Homeoprotein Differentially Promotes ex vivo Expansion of Early Human Lymphoid Progenitors

¹ Institut Cochin, Département d'Hématologie, Paris F-75014 France; INSERM, U567 Paris, F-75014 France; CNRS, UMR 8104 Paris, F-75014 France; Université Paris 5, Faculté de Médecine René Descartes, UM 3, Paris, F-75014 France; Université Paris-Sud 11, Faculté de Médecine Paris-Sud 11, le Kremlin-Bicêtre, F-94276 France
² Institut Cochin, Département d'Hématologie, Paris F-75014 France; INSERM, U567 Paris, F-75014 France; CNRS, UMR 8104 Paris, F-75014 France; Université Paris 5, Faculté de Médecine René Descartes, UM 3, Paris, F-75014 France
³ INSERM, U753, Institut Gustave Roussy, Villejuif, F-94805 France
⁴ Institut Cochin, Département d'Hématologie, Paris F-75014 France; INSERM, U567 Paris, F-75014 France; CNRS, UMR 8104 Paris, F-75014 France; Université Paris 5, Faculté de Médecine René Descartes, UM 3, Paris, F-75014 France; 7CIC Biothérapies CBT507, Institut Gustave Roussy, Villejuif, F-94805 France

^* To whom correspondence should be addressed. E-mail: fichelson{at}cochin.inserm.fr.

	Abstract

The HOXB4 homeoprotein is known to promote the expansion of mouse and human hematopoietic stem cells (HSCs) and progenitors of the myeloid lineages. However, the putative involvement of HOXB4 in lymphopoiesis and particularly in the expansion of early lymphoid progenitor cells remained elusive. Based on the ability of the HOXB4 protein to passively enter hematopoietic cells, our group previously designed a long-term culture procedure of human HSCs that allows ex vivo expansion of these cells. Here, this method has been further used to investigate whether HOXB4 could cause similar expansion on cells originating from CD34⁺ hematopoietic progenitor cells (HPCs) committed at various levels toward the lymphoid lineages. We provide evidence that HOXB4 protein delivery promotes the expansion of primitive HPCs that generate lymphoid progenitors. Moreover, HOXB4 acts on lympho-myeloid HPCs and committed T/NK HPCs but not on primary B-cell progenitors. Our results clarify the effect of HOXB4 in the early stages of human lymphopoiesis emphasizing the contribution of this homeoprotein in the maintenance of the intrinsic lympho-myeloid differentiation potential of defined HPC subsets. Finally, this study supports the potential use of HOXB4 protein for HSC and HPC expansion in a therapeutic setting and furthers our understanding of the mechanisms of the molecular regulation of hematopoiesis.