Matsumura I, Kanakura Y, Kato T, Ikeda H, Horikawa Y, Ishikawa J, Kitayama H, Nishiura T, Tomiyama Y, Miyazaki H, Matsuzawa Y
Second Department of Internal Medicine, Osaka University Medical School, Japan.
Blood. 1996 Oct 15;88(8):3074-82.
Thrombopoietin (TPO) is implicated as a primary regulator of megakaryopoiesis and thrombopoiesis. However, the biologic effects of TPO on human acute myeloblastic leukemia (AML) cells are largely unknown. To determine if recombinant human (rh) TPO has proliferation-supporting and differentiation-inducing activities in AML cells, 15 cases of AML cells that were exclusively composed of undifferentiated leukemia cells and showed growth response to rhTPO in a short-term culture (72 hours) were subjected to long-term suspension culture with or without rhTPO. Of 15 cases, rhTPO supported proliferation of AML cells for 2 to 4 weeks in 4 cases whose French-American-British subtypes were M0, M2, M4, and M7, respectively. In addition to the proliferation-supporting activity, rhTPO was found to induce AML cells to progress to some degree of megakaryocytic differentiation at both morphologic and surface-phenotypic level in 2 AML cases with M0 and M7 subtypes. The treatment of AML cells with rhTPO resulted in rapid tyrosine phosphorylation of the TPO-receptor, c-mpl, and STAT3 in all of cases tested. By contrast, the expression of erythroid/megakaryocyte-specific transcription factors (GATA-1, GATA-2, and NF-E2) was markedly induced or enhanced in only 2 AML cases that showed megakaryocytic differentiation in response to rhTPO. These results suggested that, at least in a fraction of AML cases, TPO could not only support the proliferation of AML cells irrespective of AML subtypes, but could also induce megakaryocytic differentiation, possibly through activation of GATA-1, GATA-2, and NF-E2.
血小板生成素（TPO）被认为是巨核细胞生成和血小板生成的主要调节因子。然而，TPO对人类急性髓性白血病（AML）细胞的生物学效应在很大程度上尚不清楚。为了确定重组人（rh）TPO在AML细胞中是否具有增殖支持和诱导分化活性，将15例仅由未分化白血病细胞组成且在短期培养（72小时）中对rhTPO有生长反应的AML细胞进行有或无rhTPO的长期悬浮培养。在15例中，rhTPO在4例法国-美国-英国亚型分别为M0、M2、M4和M7的病例中支持AML细胞增殖2至4周。除了增殖支持活性外，在2例M0和M7亚型的AML病例中，发现rhTPO在形态学和表面表型水平上诱导AML细胞向一定程度的巨核细胞分化。用rhTPO处理AML细胞导致所有测试病例中TPO受体c-mpl和STAT3迅速酪氨酸磷酸化。相比之下，仅在2例对rhTPO有巨核细胞分化反应的AML病例中，红系/巨核细胞特异性转录因子（GATA-1、GATA-2和NF-E2）的表达明显诱导或增强。这些结果表明，至少在一部分AML病例中，TPO不仅可以支持AML细胞的增殖而不考虑AML亚型，还可以诱导巨核细胞分化，可能是通过激活GATA-1、GATA-2和NF-E2。
