Begley C G, Rasko J E, Curtis D, Takagi K, Metcalf D, Hilton D, Roberts B, Nicola N A, Rossner M T
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Exp Hematol. 1996 Aug;24(10):1247-57.
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.
自我更新的细胞分裂是正常造血干细胞和白血病细胞群体所共有的一个重要特征。我们研究了fms样酪氨酸激酶3/胎儿肝脏激酶2配体（FL）在M1白血病细胞生长因子诱导分化过程中对自我更新的生理抑制作用。未受刺激的M1细胞表达高水平的fms样酪氨酸激酶3受体mRNA和蛋白，细胞表面约有20,000个分子。与从正常巨噬细胞群体获得的数据一致，随着细胞在白血病抑制因子（LIF）作用下被诱导分化为成熟巨噬细胞，fms样酪氨酸激酶3受体的mRNA和蛋白表达均受到抑制。虽然单独的FL对未受刺激的M1细胞没有可检测到的作用，但在LIF诱导的分化过程中显示出了一种效应。FL克服了M1细胞克隆培养中LIF诱导的抑制作用，阻止了与巨噬细胞分化相关的形态学变化，并干扰了M1细胞对巨噬细胞集落刺激因子（M-CSF）的LIF诱导反应性。FL的这种作用在亲代M1细胞和其分化程序因转录因子SCL的强制表达而受到干扰的M1细胞中均很明显。FL的作用在克隆转移实验中最为显著，在该实验中FL将M1细胞从LIF诱导的自我更新抑制中拯救出来。FL维持自我更新特征的能力满足了预测的干细胞活性分子的一个标准，并且与FL在刺激正常造血细胞增殖和分化中的作用形成对比。
