Lotem J, Sachs L
Department of Genetics, Weizmann Institute of Science, Rehovot, Israel.
Blood. 1988 Feb;71(2):375-82.
The normal myeloid hematopoietic regulatory proteins include one class of proteins that induces viability and multiplication of normal myeloid precursor cells to form colonies (colony-stimulating factors [CSF] and interleukin 3 [IL-3], macrophage and granulocyte inducing proteins, type 7 [MGI-1]) and another class (called MGI-2) that induces differentiation of normal myeloid precursors without inducing cell multiplication. Different clones of myeloid leukemic cells can differ in their response to these regulatory proteins. One type of leukemic clone can be differentiated in vitro to mature cells by incubating with the growth-inducing proteins granulocyte-macrophage (GM) CSF or IL-3, and another type of clone can be differentiated in vitro to mature cells by the differentiation-inducing protein MGI-2. We have now studied the ability of different myeloid regulatory proteins to induce the in vivo differentiation of these different types of mouse myeloid leukemic clones in normal and cyclophosphamide-treated mice. The results show that in both types of mice (a) the in vitro GM-CSF- and IL-3-sensitive leukemic cells were induced to differentiate to mature cells in vivo in mice injected with pure recombinant GM-CSF and IL-3 but not with G-CSF, M-CSF, or MGI-2; (b) the in vitro MGI-2-sensitive leukemic cells differentiated in vivo by injection of MGI-2 and also, presumably indirectly, by GM-CSF and IL-3 but not by M-CSF or G-CSF; (c) in vivo induced differentiation of the leukemic cells was associated with a 20- to 60-fold decrease in the number of blast cells; and (d) all the injected myeloid regulatory proteins stimulated the normal myelopoietic system. Different normal myeloid regulatory proteins can thus induce in vivo terminal differentiation of leukemic cells, and it is suggested that these proteins can have a therapeutic potential for myeloid leukemia in addition to their therapeutic potential in stimulating normal hematopoiesis.
正常髓系造血调节蛋白包括一类能诱导正常髓系前体细胞存活和增殖以形成集落的蛋白（集落刺激因子[CSF]和白细胞介素3[IL-3]、巨噬细胞和粒细胞诱导蛋白7型[MGI-1]）以及另一类（称为MGI-2）能诱导正常髓系前体细胞分化而不诱导细胞增殖的蛋白。不同克隆的髓系白血病细胞对这些调节蛋白的反应可能不同。一种类型的白血病克隆可通过与生长诱导蛋白粒细胞-巨噬细胞（GM）CSF或IL-3孵育在体外分化为成熟细胞，另一种类型的克隆可通过分化诱导蛋白MGI-2在体外分化为成熟细胞。我们现在研究了不同髓系调节蛋白在正常和环磷酰胺处理的小鼠体内诱导这些不同类型小鼠髓系白血病克隆分化的能力。结果表明，在这两种类型的小鼠中：（a）体外对GM-CSF和IL-3敏感的白血病细胞，在注射纯重组GM-CSF和IL-3而非G-CSF、M-CSF或MGI-2的小鼠体内被诱导分化为成熟细胞；（b）体外对MGI-2敏感的白血病细胞，通过注射MGI-2在体内分化，也可能间接通过GM-CSF和IL-3分化，但不通过M-CSF或G-CSF分化；（c）白血病细胞在体内的诱导分化与原始细胞数量减少20至60倍相关；（d）所有注射的髓系调节蛋白均刺激正常髓系造血系统。因此，不同的正常髓系调节蛋白可在体内诱导白血病细胞终末分化，提示这些蛋白除了在刺激正常造血方面具有治疗潜力外，对髓系白血病也可能具有治疗潜力。
