Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California-Los Angeles School of Medicine, CA 90048, USA.
Blood. 2010 Feb 4;115(5):1049-53. doi: 10.1182/blood-2009-03-210377. Epub 2009 Dec 2.
To elucidate whether tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia is associated with characteristic genomic alterations, we analyzed DNA samples from 45 TKI-resistant chronic myeloid leukemia patients with 250K single nucleotide polymorphism arrays. From 20 patients, matched serial samples of pretreatment and TKI resistance time points were available. Eleven of the 45 TKI-resistant patients had mutations of BCR-ABL1, including 2 T315I mutations. Besides known TKI resistance-associated genomic lesions, such as duplication of the BCR-ABL1 gene (n = 8) and trisomy 8 (n = 3), recurrent submicroscopic alterations, including acquired uniparental disomy, were detectable on chromosomes 1, 8, 9, 17, 19, and 22. On chromosome 22, newly acquired and recurrent deletions of the IGLC1 locus were detected in 3 patients, who had previously presented with lymphoid or myeloid blast crisis. This may support a hypothesis of TKI-induced selection of subclones differentiating into immature B-cell progenitors as a mechanism of disease progression and evasion of TKI sensitivity.
为了阐明慢性髓性白血病中的酪氨酸激酶抑制剂（TKI）耐药是否与特征性的基因组改变有关，我们分析了 45 例 TKI 耐药慢性髓性白血病患者的 250K 单核苷酸多态性阵列的 DNA 样本。在 20 例患者中，有预处理和 TKI 耐药时间点的匹配系列样本。在 45 例 TKI 耐药患者中，有 11 例存在 BCR-ABL1 突变，包括 2 例 T315I 突变。除了已知的与 TKI 耐药相关的基因组病变，如 BCR-ABL1 基因的重复（n=8）和 8 号染色体三体（n=3），在 1 号、8 号、9 号、17 号、19 号和 22 号染色体上还可检测到获得性单亲二体性和反复出现的亚微结构改变。在 3 例先前表现为淋巴细胞或髓系急变的患者中，在 22 号染色体上检测到新获得和反复出现的 IGLC1 基因座缺失。这可能支持 TKI 诱导的向不成熟 B 细胞祖细胞分化的亚克隆选择作为疾病进展和逃避 TKI 敏感性的机制的假说。
