Linkage of proliferative and maturational abnormalities in chronic myelogenous leukemia and relevance to treatment.
Linkage of proliferative and maturational abnormalities in chronic myelogenous leukemia and relevance to treatment.
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作者：
B. Clarkson;A. Strife
尽管我们对慢性粒细胞白血病（CML）的分子和生物学异常的理解最近取得了进展，但这些新知识尚未导致治疗的显着改善。我们已经审查了什么是已知的，仍然是未知的分子和生物学异常的CML，可能是相关的开发改进，更有选择性的治疗。CML起源于多能干细胞，因为其获得了9号和22号染色体之间高度一致的特异性染色体易位;这导致融合的bcr/abl基因和异常的210 kDa融合蛋白，与正常的c-abl蛋白相比，该融合蛋白具有增加的内在蛋白酪氨酸激酶活性。p210 bcr-abl如何改变信号转导通路尚不清楚，但主要的生物学异常是不协调或异步成熟，细胞质通常比细胞核成熟得更快。CML群体的主要扩增发生在中期和晚期成熟区室中，而不是在干细胞或早期祖细胞区室中。细胞的增殖是缓慢的，可能需要几年的时间才能达到1万亿或更多的细胞，这时临床症状开始发展。成熟的白血病祖细胞没有增加的增殖率，但它们经历一次或多次额外的分裂，并且比可比较的正常祖细胞活得更长。我们能够研究的最早期CML原始细胞群体与可比较的原始正常原始细胞群体相比，其最终增殖能力降低。虽然没有定量的干细胞检测，但间接证据表明CML干细胞的生物学行为可能相对不受影响或仅略微偏离正常。bcr/abl基因及其融合蛋白是开发新型特异性治疗的有希望的靶点，但在此之前，有必要更全面地了解分子和生化异常，并将其与疾病的生物学表现联系起来。
Despite recent advances in our understanding of the molecular and biological abnormalities in chronic myelogenous leukemia (CML) this new knowledge has not yet led to significant improvements in treatment. We have reviewed what is known and still unknown about the molecular and biological abnormalities in CML that may be relevant to developing improved, more selective treatment. CML originates in a multipotential stem cell due to its acquiring a highly consistent specific chromosomal translocation between chromosomes 9 and 22; this results in a fused bcr/abl gene and an abnormal 210 kDa fusion protein which has increased intrinsic protein tyrosine kinase activity compared to the normal c-abl protein. It is still unknown how p210bcr-abl alters the signal transduction pathways, but the main biological abnormality is discordant or asynchronous maturation, with the cytoplasm generally maturing more rapidly than the nucleus. The major expansion of the CML population takes place in the intermediate and later maturation compartments rather than in the stem cell or early progenitor cell compartments. The expansion occurs slowly, probably taking several years to reach a trillion or more cells, at which time clinical symptoms begin to develop. The maturing leukemic progenitors do not have an increased proliferative rate, but they undergo one or more additional divisions and also live longer than comparable normal progenitors. The earliest CML blast cell population we have been able to study has reduced ultimate proliferative capacity compared to a comparable primitive normal blast cell population. Although no quantitative stem cell assay is available, indirect evidence suggests that the CML stem cells' biological behavior may be relatively unaffected or deviate only slightly from normal. The bcr/abl gene and its fusion protein are promising targets for development of novel specific therapies, but before this can be accomplished it will be necessary to understand more completely the molecular and biochemical abnormalities and to correlate them with the biological manifestations of the disease.