酪氨酸激酶异常活化在恶性血液病发病中的作用(1)(精)

酪氨酸激酶异常活化在恶性血液病发病

中的作用(1)

】蛋白酪氨酸激酶（protein tyrosine kinase, PTK）在调节细胞生长、活化和分化的信号转导中起着重的作用。基因突变（多半由染色体移位）或者激酶的过度表达可使PTK活力异常增高，并介导异常的信号转导途径，在多种恶性血液病的发生发展中起着主的作用。在慢性骨髓增殖性疾病（CMPD）、急性髓性白血病（AML）和间变性大细胞淋巴瘤的发病中，均存在着PTK的异常活化。进一步研究PTK相关的恶性血液病的发病机理，可以加快特异性的分子靶向治疗的研究进展。

【关键词】酪氨酸激酶恶性血液病；基因突变

Abnormal Activation of Tyrosine Kinases and Its Role in the Pathogenesis of Hematological Malignancies ——Review

Abstract

Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiation. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) or overexpression of these enzymes plays an etiologic role in several clonal hematopoietic malignancies. Other than the causative effect of PTK product of the bcr/abl fusion gene on chronic myelogenous leukemia (CML), more evidence suggests that mutated tyrosine kinases are pivotal in the pathogenesis of most of other chronic myeloproliferative disorders, such as chronic myelomonocytic leukemia (CMML) and hypereosinophilic syndrome (HES). And the exciting results in several dependent groups in 2005 showed that a single nucleotide JAK2 somatic mutation

(JAK2V617F mutation) was found to be involved in the pathogenesis of polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (CIMF). In the leukogenesis of acute myeloid leukemias (AML), the losing of the control of the proliferation of hematopoietic progenitor cells was principally the results of the aberrant PTK activity, such as FLT3 and C kit overexpression. It works together with the loss of function mutation genes in promoting progenitor cell differentiation to confer AML's phenotypes. These upregulated PTK molecules represent attractive disease specific

targets, to which a new class of therapeutic agents are being developed. This review focuses on abnormal tyrosine kinases that have been involved in the pathogenesis of hematopoietic malignancies.

Key words

protein tyrosine kinase; hematopoietic malignancy; gene mutation

蛋白酪氨酸激酶（protein tyrosine kinase, PTK）活力增高，介导的异常的信号转导途径在多种恶性血液病的发生发展中起着主的作用［1］。造血干细胞水平PTK相关基因的活化性突变，引起配体非依赖性信号途径活化，从而使细胞呈现生长因子非依赖性生长，即恶性转化。基因突变通常由染色体移位引发PTK的异常活化，如bcr/abl融合基因与慢性髓性白血病(CML)发病的因果关系；另外，基因突变也可以由PTK本身不同结构域基因突变导致抑制其活化的基因缺失而引发，如FLT3内部串联重复与急性髓性白血病（AML）的关系。现按病种分述如下。

PTK突变与慢性骨髓增殖性疾病（CMPD）

STI571研究的成功，使得PTK在其他恶性血液病发病中所起的作用引起空前的关注。PTK异常活化介导肿瘤性信号转导途径，已经在部分的慢性骨

髓增殖性疾病(CMPD)中得以阐明。除了bcr/abl融合基因与慢性髓性白血病这一已为人们熟知的例子外，CMPD中越来越多的PTK相关的异常信号转导被发现，近期JAK2基因突变在真性红细胞增多症等CMPD发病中的作用更是引起广泛关注。

Ph染色体是CML的特殊标记，bcr/abl融合基因由９和22号染色体相互易位形成，其中abl基因编码一个非受体型PTK。由于位于22号染色体上的bcr基因断裂位置的不同，形成3种不同长度的bcr/abl融合基因，并相应地

形成3种不同分子量的蛋白产物。最常见的是P210BCR ABL，它见于95%的CML患者和1/3的Ph阳性的急性淋巴细胞白血病（ALL）患者；P190BCR ABL 见于其余2/3的Ph阳性ALL患者；P230BCR ABL见于Ph阳性的慢性中性粒

细胞白血病（CNL）患者。

P210BCR ABL 和P190BCR ABL的PTK活力明显高于正常的ABL蛋白产物。单是bcr abl融合基因产物就足以使实验动物发生CML样的骨髓增殖性疾病。例如，小鼠接受P210BCR ABL 转染的骨髓细胞后，在造血重建过程中发生骨髓增殖性疾病。P190BCR ABL转染胚胎干细胞也可引起小鼠发生

类似的病变。