Different proliferative and survival capacity of CLL-cells in a newly established in vitro model for pseudofollicles.
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B-lymphocytes that manifests in a variety of clinical courses. The accumulation of CLL-cells is primarily caused by defective apoptosis; however, a higher proliferative capacity has also been found to correlate with poorer prognostic factors. Proliferating CLL-cells are confined to specialized structures called pseudofollicles, which contain CLL-cells, T-lymphocytes, and stromal cells. We established an in vitro model for pseudofollicles to characterize the behavior of CLL-cells in relation to clinical courses with different outcomes. Only CLL-cells from progressive clinical cases were inducible to proliferate by a combination of soluble CD40L/IL-2/IL-10 in co-culture with stromal cells. Proliferating CLL-cells showed a higher and more extensive expression of antigens, which are important in T-B-cell interactions such as CD40, MHC II, and adhesion molecules. IL-4 increased interferon regulatory factor-4 expression and induced a specific immunophenotype, which may imply plasmacytic differentiation. Furthermore, it was shown that co-cultured stromal cells protected CLL-cells from apoptosis. CLL-cells from clinically indolent cases had a far worse survival rate in medium than the cells from poor prognostic cases. Thus, we can assume that not only a different resistance to apoptosis, but also proliferation contributes to the progression of CLL resulting in bone marrow failure with thrombocytopenia and anemia.
Plander
M
M
Institute of Pathology, University of Regensburg, Regensburg, Germany.
Seegers
S
S
Ugocsai
P
P
Diermeier-Daucher
S
S
Iványi
J
J
Schmitz
G
G
Hofstädter
F
F
Schwarz
S
S
Orsó
E
E
Knüchel
R
R
Brockhoff
G
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001853:Bone Marrow / Q000473:pathology*; D023201:CD40 Ligand / Q000494:pharmacology; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003470:Culture Media / Q000494:pharmacology; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017154:Stromal Cells / Q000166:cytology; D013921:Thrombocytopenia / Q000473:pathology*
D003470:Culture Media; D007376:Interleukin-2; D016753:Interleukin-10; D023201:CD40 Ligand; D015847:Interleukin-4