Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) is a disease of an accumulation of mature B cells that are highly dependent on the microenvironment for maintenance and expansion. However, little is known regarding the mechanisms whereby CLL cells create their favorable microenvironment for survival. High-mobility group protein B-1 (HMGB1) is a highly conserved nuclear protein that can be actively secreted by innate immune cells and passively released by injured or dying cells. We found significantly increased HMGB1 levels in the plasma of CLL patients compared with healthy controls, and HMGB1 concentration is associated with absolute lymphocyte count. We therefore sought to determine potential roles of HMGB1 in modulating the CLL microenvironment. CLL cells passively released HMGB1, and the timing and concentrations of HMGB1 in the medium were associated with differentiation of nurse-like cells (NLCs). Higher CD68 expression in CLL lymph nodes, one of the markers for NLCs, was associated with shorter overall survival of CLL patients. HMGB1-mediated NLC differentiation involved internalization of both receptor for advanced glycation end products (RAGE) and Toll-like receptor-9 (TLR9). Differentiation of NLCs can be prevented by blocking the HMGB1-RAGE-TLR9 pathway. In conclusion, this study demonstrates for the first time that CLL cells might modulate their microenvironment by releasing HMGB1.
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Li
L
Jia
Andrew
A
Clear
Feng-Ting
FT
Liu
Janet
J
Matthews
Nadiha
N
Uddin
Aine
A
McCarthy
Elena
E
Hoxha
Catherine
C
Durance
Sameena
S
Iqbal
John G
JG
Gribben
D015153:Blotting, Western; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D046888:Tissue Array Analysis; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
D017077:Culture Media, Conditioned; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D000067759:Receptor for Advanced Glycation End Products; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9