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

正常和肿瘤造血细胞生长的调节——BRMS 的作用

• 批准号: 3916663
• 负责人: F W RUSCETTI
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3916663
• 关键词: 1,25 dihydroxycholecalciferol; T lymphocyte; cell differentiation; cell growth regulation; clone cells; genetic transcription; hematopoiesis; hematopoietic stem cells; human tissue; immune adherence reaction; immunofluorescence technique; interleukin 2; interleukin 3; leukocyte activation /transformation; lymphokines; monoclonal antibody; myelogenous leukemia; neoplasm /cancer immunology; neoplastic cell; neoplastic growth; oncogenes; phosphatidylinositols; protein kinase C; radiotracer; transforming growth factors; viral carcinogenesis

In studying negative regulation of hematopoietic cell growth, we have found that transforming growth factor beta is a potent inhibitor. TGF-beta1 and TGF-beta2 are equipotent inhibitors which have a selective effect on hematopoiesis by halting the growth of only early human and murine progenitors. By using immature murine hematopoietic cells that respond to IL 3, it was shown that TGF- beta acted directly on the cells to block multipotent cell development but not unipotent cell growth. The earliest measurable events in vitro such as high proliferative potential colony formation (HPP-CFU) and induction of Thy-l antigen were also inhibited by TGF-beta. In contrast, there was no effect on G-CSF stimulation of granulopoiesis. In euthyroid development, CFU-GEMM and BFU-E but not CFU-E were inhibited. Thus, the ability of TGF- B to block hematopoietic progenitor cell growth depends on the differentiated state of the cell and suggests that TGF-beta is an important regulator of hematopoiesis. Fresh AML and CML as well as early myeloid leukemic cell lines retained sensitivity to positive stimulation of CSFs and negative inhibition by TGF-beta. The lone exception was HL-60, a human promyelocytic cell line, which was found not to have receptors for TGF-beta. However, agents that stimulate differentiation of HL-60 caused a reappearance of the TGF-beta receptors on the cell surface. These results suggest that the unresponsiveness to agents can be overcome in leukemic cells. In contrast to myeloid leukemic cells, cultured lymphoid leukemic cells were insensitive to TGF-S inhibition, whereas normal lymphoid cells are sensitive to TGF-B. Thus, this loss of negative regulation may play a role in the growth of some leukemic and malignant lymphoid cells.

在研究造血细胞生长的负调控时，我们 发现转化生长因子β是一种有效的 抑制剂. TGF-β 1和TGF-β 2是等效抑制剂， 对造血有选择性的影响， 只有早期的人类和鼠的祖先。 通过使用未成熟的小鼠， 造血细胞对IL 3的反应，显示TGF-β β直接作用于细胞，阻断多能细胞 但不是单能细胞生长。 最早可测量的 体外事件，如高增殖潜力集落 HPP-CFU的形成和Thy-1抗原的诱导 被TGF-β抑制。 与此相反，对G-CSF没有影响， 刺激粒细胞生成。 在甲状腺功能正常的发育中，CFU-GEMM BFU-E和CFU-E均受抑制，而CFU-E无明显变化。 因此，TGF-β的能力 B阻断造血祖细胞生长依赖于 细胞的分化状态，并表明TGF-β是一种 造血作用重要调节因子。 新鲜的AML和CML 因为早期髓系白血病细胞系对 CSF的阳性刺激和TGF-β的阴性抑制。 唯一的例外是HL-60，一种人类早幼粒细胞细胞系， 它被发现没有TGF-β受体。 然而，在这方面， 刺激HL-60分化的药物可引起 TGF-β受体在细胞表面的重现。 这些 结果表明，可以克服对药物的无反应性 在白血病细胞中。 与髓系白血病细胞相比，培养的 淋巴样白血病细胞对TGF-β抑制不敏感， 而正常淋巴样细胞对TGF-β敏感。 因此， 负调控的丧失可能在一些生长中发挥作用， 白血病和恶性淋巴细胞。