Derivative chromosome 9 deletions in chronic myeloid leukemia:: poor prognosis is not associated with loss of ABL-BCR expression, elevated BCR-ABL levels, or karyotypic instability
Derivative chromosome 9 deletions in chronic myeloid leukemia:: poor prognosis is not associated with loss of ABL-BCR expression, elevated BCR-ABL levels, or karyotypic instability
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DOI：
10.1182/blood.v99.12.4547
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发表时间：
2002-06-15
期刊：
影响因子：
20.3
通讯作者：
Green, AR
中科院分区：
文献类型：
--
作者：
Huntly, BJP;Bench, AJ;Green, AR
最近在慢性髓性白血病中报道了衍生染色体9的缺失。这些缺失很大，发生在费城（Ph）易位时，跨越易位断点，并且代表了一个强大的预后指标。然而，与缺失相关的不良预后的分子机制尚不清楚，本文研究了几种可能的模型。首先，我们证明了通过荧光原位杂交检测到的所有衍生9号染色体缺失都与ABL-BCR表达缺失相关。然而，ABL-BCR表达的缺失也发生在没有明显缺失的情况下，这表明存在其他机制可以消除ABL-BCR转录。此外，对160例患者的生存分析表明，与缺失状态相比，ABL-BCR表达缺失并不是预后不良的指标。其次，我们解决了伴随的Ph染色体小缺失调节BCR-ABL转录的可能性。实时反转录聚合酶链反应证实，衍生的9号染色体缺失并不伴随着BCR-ABL转录物水平的改变。第三，缺失可能是Ph易位时靶细胞内遗传不稳定的结果，预后不良反映了后续额外遗传改变的易感。然而，缺失的患者在疾病进展后继发性细胞遗传学改变的频率并未增加。综上所述，这些数据支持一个模型，即衍生染色体9的缺失由于缺失区域内一个或多个基因的丢失而导致疾病的快速进展。(C) 2002年由美国血液病学会出版。
Deletions of the derivative chromosome 9 have recently been reported in chronic myeloid leukemia. These deletions are large, occur at the time of the Philadelphia (Ph) translocation, span the translocation breakpoint, and represent a powerful prognostic indicator. However, the molecular mechanisms responsible for the poor prognosis associated with deletions are obscure, and several possible models are investigated here. First, we demonstrate that all derivative chromosome 9 deletions detected by fluorescence in situ hybridization were associated with an absence of ABL-BCR expression. However, loss of ABL-BCR expression also occurred without an overt deletion, suggesting the existence of other mechanisms by which ABL-BCR transcription can be abolished. Furthermore, analysis of survival in 160 patients demonstrated that loss of ABL-BCR expression, in contrast to deletion status, was not an indicator of poor prognosis. Second, we addressed the possibility that concomitant small deletions of the Ph chromosome modulate BCR-ABL transcription. Real-time reverse-transcription polymerase chain reaction was used to demonstrate that derivative chromosome 9 deletions were not accompanied by altered levels of BCR-ABL transcripts. Third, deletions may represent a consequence of genetic instability within the target cell at the time of the Ph translocation, with the poor prognosis reflecting a predisposition to subsequent additional genetic alterations. However, patients with deletions do not exhibit an increased frequency of secondary cytogenetic changes following disease progression. Taken together, these data support a model in which deletions of the derivative chromosome 9 result in rapid disease progression as a result of the loss of one or more genes within the deleted region. (C) 2002 by The American Society of Hematology.