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Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia

Julia C. Gutjahr, Eva Szenes, Lisa Tschech, Daniela Asslaber, Michaela Schlederer, Simone Roos, Xiaobing Yu, Tamara Girbl, Christina Sternberg, Alexander Egle, Fritz Aberger, Ronen Alon, Lukas Kenner, Richard Greil, Veronique Orian-Rousseau and Tanja N. Hartmann

Key points

  • The spleen but not bone marrow microenvironment induces CD44v6 variants in chronic lymphocytic leukemia, which promote early engraftment.

  • CD44v6 expression is linked to NF-kB and MAP kinase signaling in murine and human B cell leukemia and contributes to proliferation.

Abstract

Chronic lymphocytic leukemia (CLL) outgrowth depends on signals from the microenvironment. We have previously found that in vitro reconstitution of this microenvironment induces specific variant isoforms of the adhesion molecule CD44, which confer human CLL with high affinity to hyaluronan (HA). Here, we determined the in vivo contribution of standard CD44 and its variants to leukemic B-cell homing and proliferation in Tcl1 transgenic mice with a B-cell-specific CD44 deficiency. In these mice, leukemia onset was delayed and leukemic infiltration of spleen, liver, and lungs, but not of bone marrow was decreased. Competitive transplantation revealed that CLL homing to spleen and bone marrow required functional CD44. Notably, enrichment of CD44v6 variants particularly in spleen enhanced CLL engraftment and proliferation, along with increased HA-binding. We recapitulated CD44v6 induction in the human disease and revealed the involvement of MAP kinase and NF-kB signaling upon CD40 Ligand and B-cell receptor stimulation by in vitro inhibition experiments and chromatin immunoprecipitation assays. The investigation of downstream signaling after CD44v6-HA engagement uncovered the activation of ERK and p65. Consequently, anti-CD44v6 treatment reduced leukemic cell proliferation in vitro in human and mouse confirming the general nature of the findings. In summary, we propose a CD44-NF-kB-CD44v6 circuit in CLL, allowing tumor cells to gain HA binding capacity and supporting their proliferation.

  • Submitted August 17, 2017.
  • Accepted January 11, 2018.