MiR221 promotes precursor B‐cell retention in the bone marrow by amplifying the PI3K‐signaling pathway in mice. Issue 6 (15th March 2018)

• Record Type: Journal Article
• Authors: Petkau, Georg; Kawano, Yohei; Wolf, Ingrid; Knoll, Marko; Melchers, Fritz
• Is Part Of: European journal of immunology. Volume 48:Issue 6(2018)
• Page Start: 975
• Page End: 989
• Publication Date: 2018-03-15
• Subjects: CXCL12 -- CXCR4 -- PreBI‐cells -- Transplantation -- VCAM1; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201747354
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Hematopoietic stem cells and lineage‐uncommitted progenitors are able to home to the bone marrow upon transplantation and reconstitute the host with hematopoietic progeny. Expression of miR221 in B‐lineage committed preBI‐cells induces their capacity to home to the bone marrow. However, the molecular mechanisms underlying miR221‐controlled bone marrow homing and retention remain poorly understood. Here, we demonstrate, that miR221 regulates bone marrow retention of such B‐cell precursors by targeting PTEN, thus enhancing PI3K signaling in response to the chemokine CXCL12. MiR221‐enhanced PI3K signaling leads to increased expression of the anti‐apoptotic protein Bcl2 and VLA4 integrin‐mediated adhesion to VCAM1 in response to CXCL12 in vitro. Ablation of elevated PI3K activity abolishes the retention of miR221 expressing preBI‐cells in the bone marrow. These results suggest that amplification of PI3K signaling by miR221 could be a general mechanism for bone marrow residence, shared by miR221‐expressing hematopoietic cells. Abstract : Expression of miR221 amplifies the activity of PI3K in response to extracellular stimulation by CXCL12. It results in increased adhesion to VCAM1 and pro survival signalling in preBI‐cells. This confers to the cells the unique capability to engraft and establish a stable cell population in bone marrow, after transplantation.