1. ¹Department of Pathology, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA, USA
2. ²Harvard Medical School, Boston, MA, USA
3. ³Department of Pediatrics, CBR Center for Biomedical Research, Boston, MA, USA
4. ⁴Division of Molecular Medicine, Department of Genetics, Children's Hospital Boston, Boston, MA, USA
5. ⁵Department of Ophthalmology and Physiology, University of California San Francisco, San Francisco, CA, USA

Correspondence: Dr LE Silberstein, Department of Pathology, The Joint Program in Transfusion Medicine, Karp Research Building, Room 10217, One Blackfan Circle, Boston, MA 02115, USA. E-mail: leslie.silberstein@childrens.harvard.edu

⁶Current address: Beth Israel Deaconess Medical Center, Boston, MA, USA.

⁷Current address: Biogen Idec, Cambridge, MA, USA.

⁸These authors contributed equally to the work.

Received 24 November 2006; Revised 24 April 2007; Accepted 25 April 2007; Published online 14 June 2007.

Abstract

Hematopoietic stem/progenitor cells (HSC/P) reside in the bone marrow in distinct anatomic locations (niches) to receive growth, survival and differentiation signals. HSC/P localization and migration between niches depend on cell–cell and cell–matrix interactions, which result from the cooperation of cytokines, chemokines and adhesion molecules. The CXCL12-CXCR4 pathway, in particular, is essential for myelopoiesis and B lymphopoiesis but the molecular mechanisms of CXCL12 action remain unclear. We previously noted a strong correlation between prolonged CXCL12-mediated focal adhesion kinase (FAK) phosphorylation and sustained pro-adhesive responses in progenitor B cells, but not in mature B cells. Although FAK has been well studied in adherent fibroblasts, its function in hematopoietic cells is not defined. We used two independent approaches to reduce FAK expression in (human and mouse) progenitor cells. RNA interference (RNAi)-mediated FAK silencing abolished CXCL12-induced responses in human pro-B leukemia, REH cells. FAK-deficient REH cells also demonstrated reduced CXCL12-induced activation of the GTPase Rap1, suggesting the importance of FAK in CXCL12-mediated integrin activation. Moreover, in FAK^flox/flox hematopoietic precursor cells, Cre-mediated FAK deletion resulted in impaired CXCL12-induced chemotaxis. These studies suggest that FAK may function as a key intermediary in signaling pathways controlling hematopoietic cell lodgment and lineage development.