A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression.
A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression.
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DOI：
10.1084/jem.20141661
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发表时间：
2015-09-21
期刊：
影响因子：
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通讯作者：
Huntly BJ
中科院分区：
文献类型：
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作者：
Giotopoulos G;van der Weyden L;Osaki H;Rust AG;Gallipoli P;Meduri E;Horton SJ;Chan WI;Foster D;Prinjha RK;Pimanda JE;Tenen DG;Vassiliou GS;Koschmieder S;Adams DJ;Huntly BJ
Giotopoulos等人。报道一种新的小鼠模型，该模型紧密模拟人类慢性粒细胞白血病的自然进展到急变期，并使用该模型来确定与bcr-abl结合，驱动疾病进展的新的候选基因和途径。高选择性ABL酪氨酸激酶抑制剂(TKIs)的引入使慢性粒细胞白血病(CML)的治疗发生了革命性的变化。然而，TKI仅在疾病的慢性期有效，对于TKI难治性CML或进展为急变期(BC)的CML缺乏有效的治疗方法。虽然CML的慢性期依赖于bcr-abl，但进展为bcr-abl需要额外的突变。然而，这些突变的身份及其影响的途径尚不清楚，这阻碍了我们确定治疗靶点和改善结果的能力。在这里，我们描述了一种新的小鼠模型，该模型允许以公正和易处理的方式识别BC进展的机制，使用基于转座子的插入突变以慢性期CML为背景。我们的BC模型是第一个忠实地概括人类CML进展的表型、细胞和分子生物学的模型。我们报告了一种识别已知和新的候选基因的异质和独特的插入模式，并证明了这些途径推动了疾病的进展，并为新的治疗策略提供了潜在的靶点。我们的模型极大地揭示了CML进展的生物学过程，并为开发候选治疗方法以改善这种高度侵袭性疾病的悲惨结果提供了有力的资源。
Giotopoulos et al. report a novel mouse model that closely mimics the natural progression of human chronic myeloid leukemia to blast crisis, and use this model to identify novel candidate genes and pathways that, in combination with BCR-ABL, drive disease progression. The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease.