A novel insertion mutation of K294RGG within BCR-ABL kinase domain confers imatinib resistance: sequential analysis of the clonal evolution in a patient with chronic myeloid leukemia in blast crisis
A novel insertion mutation of K294RGG within BCR-ABL kinase domain confers imatinib resistance: sequential analysis of the clonal evolution in a patient with chronic myeloid leukemia in blast crisis
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DOI：
10.1007/s12185-011-0766-2
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发表时间：
2011-02-01
影响因子：
2.1
通讯作者：
Kiyoi, Hitoshi
中科院分区：
文献类型：
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作者：
Sakai, Katsuya;Ishikawa, Yuichi;Kiyoi, Hitoshi
对1例慢性粒细胞白血病（CML）患者的BCR-ABL激酶结构域突变进行了顺序分析，该患者在伊马替尼和达沙替尼治疗期间表现出反复B淋巴母细胞危象（CML-BC）。我们首先在伊马替尼治疗期间的第三个BC鉴定了五个突变BCR-ABL克隆：Y253 H，G250 E，F311 L，F317 L和K294 RGG，这是由两个核苷酸突变和六个核苷酸插入产生的，并回顾性地发现其中三个（Y253 H，G250 E，K294 RGG）已经存在于第二个BC。使用K294 RGG突变BCR-ABL表达32 D细胞的体外分析显示，K294 RGG突变对伊马替尼耐药，但对达沙替尼敏感。与体外数据一致，在该患者中，通过达沙替尼治疗消除了具有K294 RGG突变的克隆。在伊马替尼治疗期间，出现并扩增了几个突变克隆，而未获得相同等位基因上的其他突变。然而，在达沙替尼处理后，野生型BCR-ABL克隆消失，并且在相同等位基因上的G250 E和Y253 H突变克隆中获得T315 I或F317 L突变，而没有出现每个单独的突变克隆。细胞遗传学和免疫球蛋白重链基因重排分析表明，所有出现在这个病人的突变克隆可能来自同一个CML克隆。
BCR-ABL kinase domain mutations were sequentially analyzed in a patient with chronic myeloid leukemia (CML) who exhibited repeated B-lymphoid blast crisis (CML-BC) during treatment with imatinib and dasatinib. We first identified five mutant BCR-ABL clones: Y253H, G250E, F311L, F317L and K294RGG, which was generated by two-nucleotide mutations and six-nucleotide insertion, at the third BC during the imatinib treatment, and retrospectively found that three of them (Y253H, G250E, K294RGG) were already present at the second BC. The in vitro analysis using K294RGG mutant BCR-ABL-expressing 32D cells revealed that K294RGG mutation was imatinib resistant but dasatinib sensitive. Consistent with the in vitro data, the clone with K294RGG mutation was eliminated by the dasatinib treatment in this patient. During the imatinib treatment, several mutant clones emerged and expanded, while additional mutations on the same allele were not acquired. However, after the dasatinib treatment, wild-type BCR-ABL clone disappeared and T315I or F317L mutation was acquired in G250E and Y253H mutant clones on the same allele without the emergence of each sole mutant clone. Cytogenetic and immunoglobulin heavy chain gene rearrangement analysis revealed that all mutant clones that appeared in this patient might be derived from the same CML clone.