Expression of thrombopoietin receptor and its functional role in human B-precursor leukemia cells with 11q23 translocation or Philadelphia chromosome
Expression of thrombopoietin receptor and its functional role in human B-precursor leukemia cells with 11q23 translocation or Philadelphia chromosome
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DOI：
10.1038/sj.leu.2401893
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发表时间：
2000-09-01
期刊：
影响因子：
11.4
通讯作者：
Nakazawa, S
中科院分区：
文献类型：
--
作者：
Iijima, K;Sugita, K;Nakazawa, S
血小板生成素（TPO）是一种造血生长因子，在正常的巨核细胞生成和血小板生成中起重要作用。尽管现在已知TPO与由c-mpl基因编码的其受体c-MpI之间的相互作用与异常骨髓细胞和正常造血干细胞的增殖和/或分化有关，但对TPO/c-MpI系统在淋巴样白血病细胞中的作用知之甚少。在本研究中，我们首先研究了c-mpl/c-MpI的表达在23人淋巴白血病细胞系（T-系4，B-系19）使用三种不同的方法。逆转录-聚合酶链反应检测c-mpl mRNA在多达20个细胞系（T-系3，B-系17），但其翻译产物，c-MpI，是证明通过Western blot只在B-系细胞系。流式细胞仪分析显示17个B系细胞系中有13个细胞表面c-MpI表达，但其高表达（>40%）仅限于9个B前体细胞系，其中8个具有11 q23易位或费城染色体（Phl），我们还证明了8个11 q23易位或Phl的细胞系中的2个在H-3-T3细胞中对TPO表现出显著的增殖反应。胸苷摄取和集落形成测定。通过TPO触发这些细胞系瞬时上调JAK-2和Shc的酪氨酸磷酸化，表明它们的受体是功能性的。从伴有Phl或11 q23易位的B前体急性淋巴细胞白血病患者分离的原代白血病细胞也显示表面c-MpI表达和对TPO的显著反应性。这些结果表明，TPO/c-MpI相互作用可能在B-前体白血病细胞，特别是具有特定染色体异常的细胞的生长调节中发挥生理作用。
Thrombopoietin (TPO) is a hematopoietic growth factor which plays a central role in normal megakaryocytopoiesis and thrombopoiesis. Although the interaction between TPO and its receptor c-MpI encoded by the c-mpl gene is now known to be implicated in the proliferation and/or differentiation of abnormal myeloid cells and normal hematopoietic stem cells, little is known about a role of the TPO/c-MpI system in lymphoid leukemia cells. In the present study, we first examined the expression of c-mpl/c-MpI in 23 human lymphoid leukemic cell lines (T-lineage 4, B-lineage 19) using three distinct methods. The c-mpl mRNA was detectable in as many as 20 cell lines (T-lineage 3, B-lineage 17) by reverse transcriptase-polymerase chain reaction, but its translated product, c-MpI, was demonstrable by Western blot only in B-lineage cell lines. Flow cytometric analysis revealed the surface c-MpI expression in 13 of 17 B-lineage cell lines, but its higher expression (>40%) was restricted in nine B-precursor cell lines, eight of which had 11q23 translocation or Philadelphia chromosome (Phl), We also demonstrated that two of eight cell lines with 11q23 translocation or Phl exhibited a significant proliferative response to TPO in the H-3-thymidine uptake and colony-forming assays. Triggering of these cell lines by TPO transiently up-regulated tyrosine phosphorylation of JAK-2 and Shc, indicating that their receptor is functional. Primary leukemia cells separated from patients with B-precursor acute lymphoblastic leukemia with Phl or 11q23 translocation also showed the surface c-MpI expression and a significant responsiveness to TPO. These results suggest that the TPO/c-MpI interaction may play a physiological role in the growth regulation of B-precursor leukemia cells particularly with specific chromosomal abnormalities.