Proliferating CLL cells express high levels of CXCR4 and CD5

Abstract

AbstractChronic Lymphocytic Leukaemia (CLL) is an incurable progressive malignancy of CD5+ B cells with a birth rate between 0.1-1% of the entire clone per day. However, the phenotype and functional characteristics of proliferating CLL cells remain incompletely understood. Here, we stained peripheral blood CLL cells for ki67 and DNA content and found that CLL cells in G1-phase have a CXCR4loCD5hiphenotype, whilst CLL cells in S/G2/M-phase express high levels of both CXCR4 and CD5. Induction of proliferationin vitrousing CD40L stimulation results in high ki67 levels in CXCR4loCD5hicells with CXCR4 expression increasing as CLL cells progress through S and G2/M-phases, whilst CXCR4hiCD5loCLL cells remained quiescent. Dye dilution experiments revealed an accumulation of Ki67hidivided cells in the CXCR4hiCD5hifraction. In Eμ-TCL1 transgenic mice, the CXCR4hiCD5hifraction expressed high levels of ki67 and was expanded in enlarged spleens of diseased animals. Human peripheral blood CXCR4hiCD5hiCLL cells express high levels of IgM and the chemokine receptors CCR7 and CXCR5 and migrated most efficiently towards CCL21. We found higher levels of CXCR4 in patients with progressive disease and the CXCR4hiCD5hifraction was expanded upon clinical relapse. Thus, this study defines the phenotype and functional characteristics of proliferating CLL cells identifying a novel subclonal population that underlies CLL pathogenesis and may drive clinical outcome.