High-affinity neurotrophin receptors and ligands promote leukemogenesis
High-affinity neurotrophin receptors and ligands promote leukemogenesis
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DOI：
10.1182/blood-2008-05-155200
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发表时间：
2009-02-26
期刊：
影响因子：
20.3
通讯作者：
Baum, Christopher
中科院分区：
文献类型：
--
作者：
Li, Zhixiong;Beutel, Gernot;Baum, Christopher
神经营养因子（NT）及其受体在神经发生和存活中起着关键作用。TRK（原肌球蛋白相关激酶）受体蛋白酪氨酸激酶（TRKA、TRKB、TRKC）是高亲和力NT受体，在多种人体组织中表达。它们在正常和恶性造血中的作用知之甚少。在一项涉及94例成人患者的前瞻性研究中，我们首次证明了3种TRKs的细胞表面表达和原发性或继发性急性白血病患者原始细胞的组成性激活。在55%的分析病例中至少表达一种TRK。我们建立了TRK表达模式和FAB分类之间的明确相关性。尽管通过逆转录聚合酶链反应（RT-PCR）在TRK序列中仅发现少数点突变，但我们在超过50%的TRKB（+）病例（16/30）中观察到BDNF（TRKB配体）的共表达。分别通过NGF和BDNF激活TRKA或TRKB，有效地将小鼠骨髓细胞从辐射诱导的凋亡中拯救出来。TRKB/BDNF或TRKA/NGF共表达诱导小鼠造血细胞白血病此外，TRKs的激活对于人和鼠白血病细胞的存活都是重要的。我们的研究结果表明，TRKs在白血病的发生中起着重要作用，并可能作为一个新的药物靶点。（血。2009; 113：2028-2037）
Neurotrophins (NTs) and their receptors play a key role in neurogenesis and survival. The TRK (tropomyosin-related kinase) receptor protein tyrosine kinases (TRKA, TRKB, TRKC) are high-affinity NT receptors that are expressed in a variety of human tissues. Their role in normal and malignant hematopoiesis is poorly understood. In a prospective study involving 94 adult patients we demonstrate for the first time cell-surface expression of the 3 TRKs and constitutive activation in blasts from patients with de novo or secondary acute leukemia. At least one TRK was expressed in 55% of the analyzed cases. We establish a clear correlation between the TRK expression pattern and FAB classification. Although only few point mutations were found in TRK sequences by reverse-transcriptase polymerase chain reaction (RT-PCR), we observed coexpression of BDNF (ligand for TRKB) in more than 50% of TRKB(+) cases (16/30). Activation of TRKA or TRKB by NGF and BDNF, respectively, efficiently rescued murine myeloid cells from irradiation-induced apoptosis. Coexpression of TRKB/BDNF or TRKA/NGF in murine hematopoietic cells induced leukemia. Moreover, activation of TRKs was important for survival of both human and murine leukemic cells. Our findings suggest that TRKs play an important role in leukemogenesis and may serve as a new drug target. (Blood. 2009; 113: 2028-2037)