Murine flt3 ligand protects M1 leukemic cells from LIF-induced differentiation and suppression of self-renewal.
Self-renewing cell divisions are an important characteristic exhibited by both normal hematopoietic stem cells and leukemic cell populations. We have examined the action of flt3/flk2 ligand (FL) on physiologic suppression of self-renewal during growth factor-induced differentiation of M1 leukemic cells. Unstimulated M1 cells expressed high levels of flt3 receptor mRNA and protein, with approximately 20,000 molecules present at the cell surface. Consistent with data obtained from normal macrophage populations, expression of both mRNA and protein for flt3 receptor was suppressed as cells were induced to differentiate into mature macrophages in response to leukemia inhibitory factor (LIF). Although FL alone had no detectable action on unstimulated M1 cells, an effect was revealed during LIF-induced differentiation. FL overcame LIF-induced suppression in clonal cultures of M1 cells, prevented morphologic changes associated with macrophage differentiation and interfered with the LIF-induced responsiveness of M1 cells to macrophage colony-stimulating factor (M-CSF). This action of FL was evident on both parental M1 cells and M1 cells whose differentiation program was perturbed by enforced expression of the transcription factor SCL. The action of FL was most striking in clone transfer experiments in which FL rescued M1 cells from LIF-induced suppression of self-renewal. The ability of FL to maintain self-renewal characteristics satisfies one of the criteria predicted for a stem-cell-active molecule and contrasts with the action of FL in stimulating proliferation and differentiation of normal hematopoietic cells.
Begley
C G
CG
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Rasko
J E
JE
Curtis
D
D
Takagi
K
K
Metcalf
D
D
Hilton
D
D
Roberts
B
B
Nicola
N A
NA
Rossner
M T
MT
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D017931:DNA Primers; D005333:Fetus; D006131:Growth Inhibitors / Q000494:pharmacology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D015470:Leukemia, Myeloid, Acute; D008099:Liver / Q000378:metabolism; D008222:Lymphokines / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000096:biosynthesis; D013698:Templates, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C084881:flt3 ligand protein; D016173:Macrophage Colony-Stimulating Factor