PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia
PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia
复制标题
Ph 样急性淋巴细胞白血病中的 PDGFRB 突变和酪氨酸激酶抑制剂耐药性。
DOI：
10.1182/blood-2017-11-817510
复制
发表时间：
2018-05-17
期刊：
影响因子：
20.3
通讯作者：
Liu, Xin
中科院分区：
文献类型：
--
作者：
Zhang, Yingchi;Gao, Yufeng;Liu, Xin
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(TKIs)有很好的反应，例如PDGFRb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。在本研究中，我们鉴定了一个新的PDGFRb融合基因，即AGGF1-PDGFRb，并在体外对其致癌潜能进行了功能鉴定。进一步对治疗期间收集的纵向样本进行基因组图谱分析发现，出现了突变PDGFRb(C843G)，该突变直接使人对所有世代的ABL TKI产生抗药性，包括伊马替尼、达沙替尼、尼洛替尼和波纳替尼。PDGFRb突变的白血病细胞对多靶点激酶抑制剂CHZ868高度敏感，这为一些对ABL TKIs耐药的患者提供了潜在的治疗选择。综上所述，我们描述了Ph样ALL中一种复杂的克隆进化模式，并确定了一种新的PDGFRb点突变，该突变导致ABL TKI治疗后白血病复发。
Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises similar to 10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRB(C843G), which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-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 PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.