PIM1 inhibition effectively enhances Plerixafor-induced HSC mobilization

Abstract

The CXCL12/CXCR4 axis regulates the interaction of hematopoietic stem cells (HSCs) with the niche and interruption of this pathway mobilizes HSCs from the bone marrow. Therefore CXCR4 antagonists like plerixafor are clinically used to collect HSCs from patients who fail to mobilize HSCs in response to G-CSF. Nevertheless plerixafor mobilization fails in 30% of the patients and the collection window lasts only 4-6h. As the CXCR4 surface expression on HSCs is regulated by the serine/threonine kinase PIM1, we aimed to improve HSC mobilization by combining CXCR4 and PIM1 inhibition. We found that CXCR4 inhibition using plerixafor leads to a compensatory upregulation of CXCR4 surface expression on HSCs. This effect can be reverted by deficiency or inhibition of PIM1. Consequently, HSC mobilization using plerixafor is strongly enhanced in Pim1-deficient mice. Likewise, treatment of WT animals with plerixafor in combination with the pan-PIM-inhibitor LGB321 leads to increased HSC mobilization. Furthermore, Cxcl-12 expression as well as CXCR4 surface expression in CXCL12-abundant reticular (CAR) cells is dramatically decreased in Pim1- deficient mice, resulting in impaired retention of HSCs. Targeting PIM kinases in combination with CXCR4 inhibition could thus improve the collection of stem cells in patients at risk for poor mobilization