REGULATION OF NORMAL AND NEOPLASTIC HEMATOPOIETIC CELL GROWTH--ROLE OF BRMS

在研究造血细胞生长的体液调节时，我们发现 转化生长因子β具有强大的双功能作用。转化生长因子 β_1和转化生长因子β_2是等价的选择性造血抑制因子 阻止早期人类和小鼠祖先的生长，但不会更多 分化的祖细胞。用纯化的小鼠造血干细胞 在用IL-3进行的单细胞检测中，结果表明转化生长因子β直接作用于 在细胞上阻止生长。原始造血细胞如高 增殖潜能集落形成细胞(HPP-CFU)和CFU-GEMM及 BFU-E在体外可被转化生长因子β抑制。因此，转化生长因子β的能力 阻断造血细胞生长依赖于细胞的分化状态 牢房。相反，在GM-CSF刺激的骨中添加转化生长因子β 骨髓细胞极大地促进了生长，主要导致了 在粒细胞中。转化生长因子β的体内实验表明， 造血干细胞被可逆地阻止进入细胞 周而复始。这种生长抑制作用至少在两个层面上起作用：1) 细胞表面受体的反式下调以实现正向调节 信号和/或干扰这些信号的受体后信号 分子。白血病细胞系对药物敏感或不敏感 转化生长因子β介导的生长抑制。肿瘤性B淋巴细胞的生长可以 通过逃离转化生长因子β介导的自分泌抑制环而发生。 激活信号(如佛波酯)可通过以下途径抑制肿瘤细胞生长 刺激活性转化生长因子β的产生和细胞表面的诱导 功能性转化生长因子β受体的表达。这些结果表明， 转化生长因子β可能具有保护骨髓和抗肿瘤的作用 探员。

In studying humoral regulation of hematopoietic cell growth, we have found that transforming growth factor beta has potent bifunctional effects. TGF beta1 and TGF beta2 are equipotent selective inhibitors of hematopoiesis that halt the growth of early human and murine progenitors but not more differentiated progenitors. Using purified murine hematopoietic stem cells in single cell assays with IL 3, it was shown that TGF beta acted directly on the cells to block growth. Primitive hematopoietic cells such as high proliferative potential colony forming cell (HPP-CFU) and CFU-GEMM and BFU-E were inhibited by TGF beta in vitro. Thus, the ability of TGF beta to block hematopoietic cell growth depends on the state of differentiation of the cell. In contrast, addition of TGF beta to GM-CSF stimulated bone marrow cells greatly augmented growth, leading predominantly to an increase in granulocytes. In vivo experiments with TGF beta show that the hematopoietic stem cells are reversibly prevented from entering the cell cycle. This growth inhibitory action functions on at least two levels: 1) trans-down modulation of the cell surface receptors for positive regulatory signals and/or interfering with post-receptor signalling of these molecules. Leukemic cell lines could be either sensitive or insensitive to TGF beta mediated growth inhibition. Growth of neoplastic B lymphocytes can occur by escaping from a TGF beta mediated autocrine inhibitory loop. Activation signals (e.g. phorbol esters) can inhibit tumor cell growth by stimulation of active TGF beta production and induction of cell surface expression of functional TGF beta receptors. These results suggest that TGFbeta may have utility as a bone marrow protective and as an anti-tumor agent.