The clinical outcomes of chronic myeloid leukemia patients harboring alternatively spliced BCR-ABL variants
The clinical outcomes of chronic myeloid leukemia patients harboring alternatively spliced BCR-ABL variants
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DOI：
10.1080/10245332.2018.1507883
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发表时间：
2019-01-01
期刊：
影响因子：
1.9
通讯作者：
Suzuki, Takahiro
中科院分区：
文献类型：
--
作者：
Ishida, Takashi;Miyazaki, Koji;Suzuki, Takahiro
目的和重要性：酪氨酸激酶抑制剂（TKI）是治疗慢性粒细胞白血病（CML）不可或缺的药物。然而，选择性剪接变异体最近被提出作为TKI耐药的机制，尽管这些突变的临床意义仍然存在争议。我们在这里提出了长期的临床课程的三个慢性粒细胞白血病患者窝藏这种独特的突变，并试图评估其临床意义。此外，外显子6移码很少报道，这可能提供了重要的信息，这种罕见的突变。临床表现：我们报告三例慢性粒细胞白血病窝藏外显子7缺失，插入35个内含子核苷酸和外显子6移码，分别。值得注意的是，所有患者在TKI给药后均获得优于分子学缓解（4.0）。讨论和结论：3例CML病例强调了此类剪接变异体与临床结局之间的相关性。由于这些突变导致的激酶结构域的过早终止可能导致构象变化并抑制TKI结合，但也导致CML细胞的激酶活性消失。因此，上述突变体可能对治疗结果的影响较小。值得注意的是，临床上可用的国际规模RT-PCR系统无法区分激酶活性突变体和激酶失活突变体，这可能会影响治疗疗效的解释。对相应突变体的克隆定量可以更准确地评估这些患者的CML状态。因此，人们应该认识到这些重要的剪接变体，并积累进一步的经验。
Objectives and importance: Tyrosine kinase inhibitors (TKIs) are indispensable for the treatment of chronic myeloid leukemia (CML). However, alternative splicing variants have been recently proposed as mechanisms of TKI resistance, although the clinical significance of these mutations remains controversial. We here present the long-term clinical courses of three CML patients harboring such unique mutations and try to assess their clinical significances. Moreover, the exon 6 frameshift presented here has been rarely reported, which may provide important information on this rare mutation. Clinical presentation: We report three cases of CML harboring an exon 7 deletion, insertion of 35 intronic nucleotides and an exon 6 frameshift, respectively. Remarkably, all patients obtained better than molecular response(4.0) following administration of TKIs. Discussion and conclusion: Three CML cases highlighted an association between such splicing variants and clinical outcomes. The premature termination in the kinase domain due to these mutations likely causes conformational changes and inhibits TKI binding, but it also results in abrogating kinase activities of CML cells. Thus, the above-mentioned mutants might less affect outcomes of treatment. Noteworthy, clinically available International Scale RT-PCR system cannot distinguish kinase-active mutants from kinase-inactive mutants, which may possibly influence upon interpretation of the treatment efficacy. Clonal quantification on respective mutants could more precisely evaluate CML status in these patients. Therefore, one should realize these important splicing variants and accumulate further experiences.