The molecular basis of leukemia.
The molecular basis of leukemia.
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DOI：
10.1182/asheducation-2004.1.80
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
D. Gilliland;C. Jordan;C. Felix
中科院分区：
文献类型：
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作者：
D. Gilliland;C. Jordan;C. Felix
我们在理解成人和儿童白血病的分子基础方面取得了重大进展。在白血病的细胞培养和小鼠模型中，已经识别和表征了100多个疾病等位基因。在某些情况下，基于这些目前处于临床试验中的见解，已经开发出分子靶向治疗，例如Flt3的小分子抑制剂。此外，最近人们认识到，与正常的造血一样，白血病细胞之间存在等级结构，其中包括具有自我更新特性的罕见的白血病干细胞群体。了解这些白血病干细胞的特征可能为针对自我更新途径的白血病治疗提供新的见解。在第一节中，克雷格·乔丹博士回顾了支持“白血病干细胞”存在的数据。他概述了白血病干细胞的功能特性，它们与造血干细胞的关系，以及白血病干细胞与包括实体瘤在内的其他人类恶性肿瘤的相关性。他简要讨论了已知的调节自我更新特性的途径。加里·吉利兰博士在第二节中概述了成人白血病的遗传学，以及正在进行的发现新疾病等位基因的全基因组战略。他描述了这些发现的临床和治疗意义，并提供了急性髓细胞白血病分子靶向治疗的床边翻译实例，包括Flt3抑制剂的使用。在第三节中，Carolyn Felix博士回顾了我们在了解儿童白血病的遗传学和治疗方面的最新进展。她概述了在儿童恶性肿瘤中常见但在成人中很少观察到的白血病，包括与儿童B细胞ALL相关的TEL-AML1(ETV6-RUNX1)融合，与婴儿巨核细胞白血病相关的OTT-MAL融合，青少年粒单核细胞白血病中的PTPN11突变，以及与白血病发生有关的MLL融合基因等。
Major strides have been made in our understanding of the molecular basis of adult and pediatric leukemias. More than one hundred disease alleles have been identified and characterized in cell culture and murine models of leukemia. In some instances, molecularly targeted therapies have been developed based on these insights that are currently in clinical trials, such as small molecule inhibitors of FLT3. In addition, it has recently been appreciated that, as with normal hematopoiesis, there is a hierarchical organization among leukemic cells that includes a rare population of leukemic stem cells that have properties of self-renewal. Understanding the characteristics of these leukemic stem cells may provide new insights into leukemia therapies that target self-renewal pathways. In Section I, Dr. Craig Jordan reviews the data that supports the existence of a "leukemia stem cell." He provides an overview of the functional properties of leukemic stem cells, their relationship to hematopoietic stem cells, and the relevance of leukemic stem cells in other human malignancies including solid tumors. He briefly discusses what is known of the pathways that regulate properties of self-renewal. Dr. Gary Gilliland provides an overview of the genetics of adult leukemias in Section II and ongoing genome-wide strategies for discovery of new disease alleles. He describes the clinical and therapeutic implications of these findings and provides examples of bench-to-bedside translation of molecularly targeted therapies for AML, including the use of FLT3 inhibitors. In Section III, Dr. Carolyn Felix reviews recent advances in our understanding of the genetics and therapy of pediatric leukemias. She provides an overview of leukemias that are common in pediatric malignancies but rarely observed in adults, including the TEL-AML1 (ETV6-RUNX1) fusion associated with pediatric B-cell ALL, the OTT-MAL fusion associated with infant megakaryoblastic leukemia, PTPN11 mutations in juvenile myelomonocytic leukemia, and MLL fusion genes in leukemogenesis, among others.