Growth mechanism of human myeloma cells by interleukin-6.
Human myeloma cells are heterogenous morphologically and phenotypically. Myeloma cells can be classified into at least 5 subpopulations; MPC-1-CD45+CD49e-, MPC-1-CD45-CD49e- immature myeloma cells, MPC-1+CD45-CD49e-, MPC-1+CD45+CD49e- intermediate myeloma cells and MPC-1+CD45+CD49e+ mature myeloma cells. Interleukin-6(IL-6) is a major growth factor for human myeloma cells, but only MPC-1-CD45+CD49e- immature myeloma cells can response directly to IL-6 to proliferate. In the U-266 cell lines, IL-6 can lead to the induction of CD45 expression and CD45+ U-266 cells can proliferate in response to IL-6. In primary myeloma cells, MPC-1-CD45-CD49e- immature myeloma cells sorted from bone marrow samples can be changed to CD45+ cells by addition of IL-6 in vitro. In both CD45- and CD45+ U-266 cells, STAT3 and MAPK(ERK1/2) can be activated in response to IL-6 equally between them, but src family kinases such as Lyn, Fyn can be activated only in CD45+ U-266 cells. Thus, the activation of the src family kinases associated with CD45 expression is a prerequisite for the proliferation of myeloma cells. In the bone marrow of myeloma patients, most myeloma cells do not express CD45, and CD45+ immature myeloma cells are only 1 approximately 2%. In order to clarify the difference of cellular context between CD45- and CD45+ myeloma cells, PCR-based cDNA subtraction was performed from CD45+ U-266 cells to CD45-U-266 cells. The series of this subtraction selected several genes. Furthermore, sensitivity to stress stimuli between CD45+ and CD45- U-266 cells was also compared. CD45-U-266 cells were markedly more resistant to stress conditions such as serum-free condition. Therefore, we can speculate that in the bone marrow of human myelomas IL-6 can induce proliferation of CD45+ immature cells, but the amount of IL-6 is too low to support CD45+ myeloma cells and loss of CD45 results in no direct response to IL-6 to proliferate but confers resistance to stress condition leading to the longer survival at the limited amount of IL-6.
Kawano
Michio M
MM
Department of Bio-Signal Analysis, AMES, Graduate School of Medicine, Yamaguchi Univ, Ube, Japan.
Ishikawa
Hideaki
H
Tsuyama
Naohiro
N
Abroun
Saeid
S
Liu
Shangqin
S
Li
Fu-Jun
FJ
Otsuyama
Ken-ichiro
K
Zheng
Xu
X
D002455:Cell Division / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000494:pharmacology*; D017493:Leukocyte Common Antigens / Q000502:physiology; D020935:MAP Kinase Signaling System; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology; D013312:Stress, Physiological; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D017493:Leukocyte Common Antigens