慢性粒细胞白血病发病机制及治疗进展(1)
[摘要] 慢性粒细胞白血病(CML)存在特征性的遗传学异常，靶向作用于Bcr—Abl融合基因编码的P210蛋白的酪氨酸激酶抑制剂，使得CML的治疗发生了革命性进展。作为第一代酪氨酸激酶抑制剂，伊马替尼明显地改善CML患者的疗效及预后，然而逐渐出现的耐药使其疗效受到了影响。随着对耐药机制的深入研究，认为Bcr—Abl激酶区基因点突变是引起伊马替尼耐药的重要原因，对此研发了第二代酪氨酸激酶抑制剂尼洛替尼及达沙替尼。尼洛替尼及达沙替尼较伊马替尼对P210融合蛋白具有更强的亲和力和抑制性，能够使各阶段CML耐药患者获得更好的缓解，并能使大部分患者获得长期的生存，但对T315I突变无效。处于临床试验中的第三代特异性分子抑制剂，如Bosutinib、Ponatinib等，能够逆转T315I所致的耐药，且能作用于Aurora激酶、SFK、LYN及SRC等其他分子靶点，有望解决更多的耐药难题。
[关键词] 慢性粒细胞白血病；发病机制；耐药；治疗
[中图分类号] R733.7 [文献标识码] A [文章编号] 1673—9701(2012)27—0009—04
, 百拇医药
The pathogenesis and therapy of chronic myeloid leukemia
LUO Mi1 OUYANG Zhao2
1.Clinical Laboratory， Yueyang Changlian Hospital of Hunan Province， Yueyang 414012， China； 2.Department of Hematology， Xiangya Hospital， Central South University， Changsha 410008， China
[Abstract] The chronic myeloid leukemia (CML) is characterized by a cytogenetic abnormality. The inhibitors of protein tyrosine kinase which targeting the protein P210 encoded by Bcr—Abl fusion protein have made a revolutionary progress in the treatment of CML. As the first—generation of tyrosine kinase inhibitors (TKIs)， imatinib obviously improves the therapeutic efficacy and the prognosis of patients with CML. However，the gradual occurrence of resistance to imatinib limits its efficacy. With the advances in the understanding of molecular mechanisms of resistance， we consider that Bcr—Abl kinase domain mutations have been extensively implicated in the pathogenesis of imatinib resistance. The limitations of imatinib have inspired the development of second—generation TKIs nilotinib and dasatinib. Compared to imatinib，nilotinib and dasatinib have stronger affinity and efficacy on P210 fusion protein，and make patients in each phase who resistant to imatinb achieving better response. Long—term survival is a reality for majority of patients，with the exception of those with the T315I mutation. The third—generation clinical candidates which targeting Aurora kinase， SFK， LYN and SRC， such as bosutinib and ponatinib，are effective salvage for patients with T315I mutation，and are expected to overcome the effect of resistance.
, 百拇医药
[Key words] Chronic myeloid leukemia； Pathogenesis； Resistance； Treatment
慢性粒细胞白血病(chronic myeloid leukemia，CML)是一种起源于多能造血干细胞的恶性骨髓增殖性疾病，占所有白血病的15%～20%，全世界年发病率(1.0～1.5)/10万，临床上分慢性期(chronic phase，CP)、加速期(accelerated phase，AP)和急变期(blastic phase，BP或blast crisis，BC)[1]。95%以上的CML患者存在特征性的遗传学异常，即t(9；22)(q34；q11)而形成的Ph染色体和/或Bcr—Abl融合基因[2]。Bcr—Abl融合基因编码的P210融合蛋白不仅是导致CML发生及进展的根本原因，也是治疗的重要靶点。目前治疗CML的主要目标是达到细胞遗传学甚至分子生物学缓解，预防疾病进展，延长生存期，提高生活质量和治愈疾病[3]。本文就CML发病机制以及在此基础上的治疗进展作一简述。
, 百拇医药(罗米 欧阳昭)
[关键词] 慢性粒细胞白血病；发病机制；耐药；治疗
[中图分类号] R733.7 [文献标识码] A [文章编号] 1673—9701(2012)27—0009—04
, 百拇医药
The pathogenesis and therapy of chronic myeloid leukemia
LUO Mi1 OUYANG Zhao2
1.Clinical Laboratory， Yueyang Changlian Hospital of Hunan Province， Yueyang 414012， China； 2.Department of Hematology， Xiangya Hospital， Central South University， Changsha 410008， China
[Abstract] The chronic myeloid leukemia (CML) is characterized by a cytogenetic abnormality. The inhibitors of protein tyrosine kinase which targeting the protein P210 encoded by Bcr—Abl fusion protein have made a revolutionary progress in the treatment of CML. As the first—generation of tyrosine kinase inhibitors (TKIs)， imatinib obviously improves the therapeutic efficacy and the prognosis of patients with CML. However，the gradual occurrence of resistance to imatinib limits its efficacy. With the advances in the understanding of molecular mechanisms of resistance， we consider that Bcr—Abl kinase domain mutations have been extensively implicated in the pathogenesis of imatinib resistance. The limitations of imatinib have inspired the development of second—generation TKIs nilotinib and dasatinib. Compared to imatinib，nilotinib and dasatinib have stronger affinity and efficacy on P210 fusion protein，and make patients in each phase who resistant to imatinb achieving better response. Long—term survival is a reality for majority of patients，with the exception of those with the T315I mutation. The third—generation clinical candidates which targeting Aurora kinase， SFK， LYN and SRC， such as bosutinib and ponatinib，are effective salvage for patients with T315I mutation，and are expected to overcome the effect of resistance.
, 百拇医药
[Key words] Chronic myeloid leukemia； Pathogenesis； Resistance； Treatment
慢性粒细胞白血病(chronic myeloid leukemia，CML)是一种起源于多能造血干细胞的恶性骨髓增殖性疾病，占所有白血病的15%～20%，全世界年发病率(1.0～1.5)/10万，临床上分慢性期(chronic phase，CP)、加速期(accelerated phase，AP)和急变期(blastic phase，BP或blast crisis，BC)[1]。95%以上的CML患者存在特征性的遗传学异常，即t(9；22)(q34；q11)而形成的Ph染色体和/或Bcr—Abl融合基因[2]。Bcr—Abl融合基因编码的P210融合蛋白不仅是导致CML发生及进展的根本原因，也是治疗的重要靶点。目前治疗CML的主要目标是达到细胞遗传学甚至分子生物学缓解，预防疾病进展，延长生存期，提高生活质量和治愈疾病[3]。本文就CML发病机制以及在此基础上的治疗进展作一简述。
, 百拇医药(罗米 欧阳昭)