State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
Blood. 2018 May 17;131(20):2256-2261. doi: 10.1182/blood-2017-11-817510. Epub 2018 Feb 6.
Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ∼10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in -rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel fusion gene, namely -, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. -mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel point mutation that drives leukemia relapse after ABL TKI treatment.
费城染色体（Ph）样急性淋巴细胞白血病（ALL）占儿童 ALL 病例的 10%至 15%，其中许多对酪氨酸激酶抑制剂（TKI）非常敏感，例如在 -重排 ALL 中的伊马替尼。然而，一些病例对 TKI 产生了耐药性，其机制尚不清楚。在这项研究中，我们鉴定了一种新的 融合基因，即 ，并在体外功能上表征了其致癌潜能。在治疗过程中对纵向采集的样本进行进一步的基因组分析揭示了一种突变 的出现，它直接赋予了对所有代 ABL TKI 的耐药性，包括伊马替尼、达沙替尼、尼洛替尼和泊那替尼。-突变的白血病细胞对多靶点激酶抑制剂 CHZ868 高度敏感，这表明对于一些对 ABL TKI 耐药的患者可能有潜在的治疗选择。总之，我们描述了 Ph 样 ALL 中的一种复杂的克隆进化模式，并鉴定了一种新的 点突变，该突变可导致 ABL TKI 治疗后白血病复发。
