Effects of anti-CD44 monoclonal antibodies on differentiation and apoptosis of human myeloid leukemia cell lines
Effects of anti-CD44 monoclonal antibodies on differentiation and apoptosis of human myeloid leukemia cell lines
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DOI：
10.1182/blood.v99.1.290
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发表时间：
2002-01-01
期刊：
影响因子：
20.3
通讯作者：
Smadja-Joffe, F
中科院分区：
文献类型：
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作者：
Charrad, RS;Gadhoum, Z;Smadja-Joffe, F
急性髓系白血病 (AML) 是一种异质性白血病，其特征是不同阶段的髓系分化受阻，从而定义了不同的 AML 亚型。我们最近报道，CD44 与 2 种激活单克隆抗体 (mAb) A3D8 和 H90 的连接，触发 AML-M1/2 中的白血病母细胞终末分化为 AML-M5 亚型，这是最常见的亚型。然而，新鲜的 AML 母细胞体外寿命较短。因此，为了找到相关的体外细胞模型来进一步研究 CD44 诱导分化的机制，我们研究了 CD44 与 A3D8 和 H90 mAb 连接是否可以诱导 THP-1、NB4 和 HL60 细胞的终末分化，分别是 AML-M5（单核细胞亚型）、AML-M3（早幼粒细胞亚型）和 AML-M2（粒细胞亚型）的有趣模型。我们还研究 CD44 连接是否会导致增殖能力丧失，这是晚期骨髓分化的一个重要特征。在我们研究的第二部分中，我们研究了 A3D8 和 H90 抗 CD44 mAb 是否可以诱导 KG1a 细胞（非常不成熟的 AML-M0 母细胞）的分化并抑制其增殖。使用功能、抗原和细胞学标准，我们目前表明 A3D8 和/或 H90 诱导 THP-1、HL60 和 NB4 细胞系的终末分化，并强烈抑制它们的增殖。有趣的是，观察到了 H90 和 A3D8 的细胞特异性作用。我们还观察到，与 A3D8 一起孵育 3 至 6 天会诱导细胞凋亡，在 THP-1 和 HL60 细胞中为中度细胞凋亡，在 NB4 细胞中为大量细胞凋亡。最后，我们的结果首次证明，通过使用抗 CD44 mAb 和视黄酸可以逆转 KG1a 细胞的白血病阻断。该结果可能为AML-M0患者的差异化治疗提供新的实验依据。
Acute myeloid leukemia (AML) is a heterogeneous leukemia characterized by the blockage of myeloid differentiation at different stages, which define distinct AML subtypes. We have recently reported that the ligation of CD44 with 2 activating monoclonal antibodies (mAbs), A3D8 and H90, triggers terminal differentiation of leukemic blasts in AML-M1/2 to AML-M5 subtypes, which are the most frequent ones. However, fresh AML blasts have short in vitro lifespans. Therefore, to find relevant in vitro cellular models for further studying the mechanisms involved in CD44-induced differentiation, we investigated whether CD44 ligation with A3D8 and H90 mAbs can induce terminal differentiation of THP-1, NB4, and HL60 cells, each interesting models of AML-M5 (monoblastic subtype), AML-M3 (promyelocytic subtype), and AML-M2 (myeloblastic subtype), respectively. We also study whether CD44 ligation induces a loss of proliferative capacity, an important feature of late-stage myeloid differentiation. In the second part of our study, we investigated whether A3D8 and H90 anti-CD44 mAbs can induce the differentiation and inhibit the proliferation of KG1a cells, which are very immature AML-M0 blasts. Using functional, antigenic, and cytologic criteria, we presently show that A3D8 and/or H90 induce terminal differentiation of THP-1, HL60, and NB4 cell lines and strongly inhibit their proliferation. Interestingly, cell-specific effects of H90 and A3D8 are observed. We also observe that Incubation with A3D8 for 3 to 6 days induces an apoptotic cell death that Is moderate In the case of THP-1 and HL60 cells and massive in the case of NB4 cells. Finally, our results demonstrate for the first time that it is possible to reverse the leukemic blockage of KG1a cells by using both an anti-CD44 mAb and retinoic acid. This result may provide a new experimental basis for a differentiative therapy in AML-M0 patients.