Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia
Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia
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DOI：
10.1182/blood-2010-08-301267
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发表时间：
2011-03-31
期刊：
影响因子：
20.3
通讯作者：
Williams, Richard T.
中科院分区：
文献类型：
--
作者：
Boulos, Nidal;Mulder, Heather L.;Williams, Richard T.
将培养的表达p185（BCR-ABL）的（p185（+））Arf（-/-）前B细胞引入健康的同基因小鼠中，诱导侵袭性急性淋巴细胞白血病（ALL），其在遗传和表型上模拟人类疾病。我们将这种高通量费城染色体阳性（Ph+）ALL动物模型用于体内发光成像，以研究活小鼠的疾病进展、靶向治疗反应和ALL复发。携带高白血病负荷的小鼠（诊断时模拟人Ph+ ALL）在最大强度、每日两次达沙替尼治疗后进入缓解期，但总是复发，伴有播散性和/或中枢神经系统疾病。尽管复发经常伴随着携带BCR-ABL激酶结构域（KD）突变的白血病克隆的最终出现，这些突变赋予耐药性，但它们的克隆出现需要长期的达沙替尼暴露。KD P环突变在接受较低强度治疗的小鼠中占主导地位，而高剂量治疗选择了对所有3种食品和药物管理局批准的BCR-ABL激酶抑制剂耐药的T315 I“看门人”突变。在降低强度的达沙替尼治疗中添加地塞米松和/或L-天冬酰胺酶改善了接受所有3种药物的大多数小鼠的长期存活率。虽然非肿瘤细胞自主机制可以防止完全根除达沙替尼难治性ALL在这个临床相关的模型，出现耐药性的BCR-ABL激酶抑制剂可以有效地规避添加“传统”化疗药物与替代抗白血病的作用机制。（血。2011;117（13）：3585-3595）
The introduction of cultured p185(BCR-ABL)-expressing (p185(+)) Arf(-/-) pre-B cells into healthy syngeneic mice induces aggressive acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease. We adapted this high-throughput Philadelphia chromosome-positive (Ph+) ALL animal model for in vivo luminescent imaging to investigate disease progression, targeted therapeutic response, and ALL relapse in living mice. Mice bearing high leukemic burdens (simulating human Ph+ ALL at diagnosis) entered remission on maximally intensive, twice-daily dasatinib therapy, but invariably relapsed with disseminated and/or central nervous system disease. Although relapse was frequently accompanied by the eventual appearance of leukemic clones harboring BCR-ABL kinase domain (KD) mutations that confer drug resistance, their clonal emergence required prolonged dasatinib exposure. KD P-loop mutations predominated in mice receiving less intensive therapy, whereas high-dose treatment selected for T315I "gatekeeper" mutations resistant to all 3 Food and Drug Administration-approved BCR-ABL kinase inhibitors. The addition of dexamethasone and/or L-asparaginase to reduced-intensity dasatinib therapy improved long-term survival of the majority of mice that received all 3 drugs. Although non-tumor-cell-autonomous mechanisms can prevent full eradication of dasatinib-refractory ALL in this clinically relevant model, the emergence of resistance to BCR-ABL kinase inhibitors can be effectively circumvented by the addition of "conventional" chemotherapeutic agents with alternate antileukemic mechanisms of action. (Blood. 2011;117(13):3585-3595)