Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to ST157, and they can pre-exist to the onset of treatment
Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to ST157, and they can pre-exist to the onset of treatment
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DOI：
10.1182/blood.v100.3.1014
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发表时间：
2002-08-01
期刊：
影响因子：
20.3
通讯作者：
Preudhomme, C
中科院分区：
文献类型：
--
作者：
Roche-Lestienne, C;Soenen-Cornu, V;Preudhomme, C
靶向BCR-ABL的酪氨酸激酶活性是一种非常有前途的治疗慢性髓性白血病（CML）的策略。尽管酪氨酸激酶抑制剂ST1571疗效显著，但在相当比例的晚期CML或ph阳性急性淋巴细胞白血病（ALL）患者中观察到耐药性。在这项研究中，我们通过酪氨酸激酶结构域的点突变和/或BCR-ABL基因扩增，研究了24例对ST1571治疗无细胞遗传学反应的患者（16例为慢性期，8例为加速期）对ST1571耐药的机制。利用逆转录聚合酶链反应限制性片段长度多态性（RT-PCR-RFLP）技术筛选已经描述的ABL结构域Thr315IIe点突变，3例患者在耐药时出现一定比例的突变转录物。同样的技术在诊断时未能检测到突变，但在DNA上对Thr315IIe突变进行特异性等位基因特异性寡核苷酸（ASO） pcr，并对2个新描述的Phe311 Leu和Met351Thr替换进行测序后，显示在ST1571治疗前存在罕见的突变细胞。此外，ASO-PCR检测到在处理过程中突变细胞比例增加，这强烈表明克隆选择是通过这些突变的功能抑制作用来实现的。最后，在24例st1571耐药患者中，荧光原位杂交（FISH）未检测到BCR-ABL基因扩增。我们的数据支持，在接受ST1571治疗的CML患者中，ABL突变并不局限于疾病的加速期，至少在某些情况下，突变似乎发生在ST1571治疗之前，可能是CML过程中的第二次突变事件。(C) 2002年由美国血液病学会出版。
Targeting the tyrosine kinase activity of BCR-ABL represents a very promising therapeutic strategy in chronic myeloid leukemia (CML). Despite strong efficacy of the tyrosine kinase inhibitor ST1571, resistance has been observed in a significant proportion of patients in advanced CML stage or in Ph-positive acute lymphoid leukemia (ALL). We investigated in this study the mechanism of resistance to ST1571 through point mutations in the tyrosine kinase domain and/or BCR-ABL gene amplification in 24 patients (16 in chronic phase and 8 in accelerated phase of the disease) who obtained no cytogenetic response to ST1571 treatment. Screening for the already-described Thr315IIe point mutation in the ABL domain using a reverse transcription polymerase chain reaction restriction fragment length polymorphism (RT-PCR-RFLP) technique, 3 patients showed a proportion of mutated transcript at the time of resistance. The same technique failed to detect mutation at diagnosis, but a specific allele-specific oligonucleotide (ASO)-PCR on DNA for the Thr315IIe mutation and, after sequencing, for 2 newly described Phe311 Leu and Met351Thr substitutions, showed the presence of rare mutated cells prior to ST1571 therapy. Furthermore, the increased proportion of mutated cells during treatment detected by ASO-PCR strongly suggested clonal selection by the functional inhibiting effect of these mutations. Finally, no BCR-ABL gene amplification was detected by fluorescent in situ hybridization (FISH) in the 24 ST1571-resistant patients. Our data support that in CML patients treated with ST1571, ABL mutations are not restricted to the accelerated phase of the disease and that, at least in some cases, mutations seem to occur prior to ST1571 therapy, probably as second mutational events during the course of CML. (C) 2002 by The American Society of Hematology.