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Type of publication: Journal Article
Type of document: Full Paper

Year: 2018

Authors: Gutjahr, JC; Szenes, E; Tschech, L; Asslaber, D; Schlederer, M; Roos, S; Yu, X; Girbl, T; Sternberg, C; Egle, A; Aberger, F; Alon, R; Kenner, L; Greil, R; Orian-Rousseau, V; Hartmann, TN

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

Source: Blood. 2018; 131(12):1337-1349

Authors Vetmeduni Vienna:

Kenner Lukas
Sternberg Christina
Tangermann Simone

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals

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 MAPK and NF-κB 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 extracellular signal-regulated kinase 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-κB-CD44v6 circuit in CLL, allowing tumor cells to gain HA binding capacity and supporting their proliferation.© 2018 by The American Society of Hematology.

Keywords Pubmed: Animals
Cell Proliferation
Hyaluronan Receptorsgeneticsmetabolism
Hyaluronic Acidgeneticsmetabolism
Leukemia, Lymphocytic, Chronic, B-Cellgeneticsmetabolismpathology
MAP Kinase Signaling System
Mice, Transgenic
NF-kappa Bgeneticsmetabolism
Neoplasm Proteinsgeneticsmetabolism
Receptors, Antigen, B-Cellgeneticsmetabolism
Tumor Microenvironment

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