Chronic myeloid leukemia cells refractory/resistant to tyrosine kinase inhibitors are genetically unstable and may cause relapse and malignant progression to the terminal disease state.
Chronic myeloid leukemia cells refractory/resistant to tyrosine kinase inhibitors are genetically unstable and may cause relapse and malignant progression to the terminal disease state.
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DOI：
10.3109/10428194.2010.546912
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发表时间：
2011-02
影响因子：
2.6
通讯作者：
Skorski T
中科院分区：
文献类型：
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作者：
Skorski T
BCR-ABL1 激酶诱导的慢性期慢性粒细胞白血病 (CML-CP) 通常对 ABL 酪氨酸激酶抑制剂 (TKI)（如伊马替尼、达沙替尼和尼洛替尼）治疗有反应。在大多数患者中，TKI 可显着降低白血病细胞负荷，但某些白血病细胞，例如白血病干细胞 (LSC) 本质上对 TKI 耐药。此外，一些最初有反应的患者可能会由于 BCR-ABL1 激酶点突变的积累而对 TKI 产生耐药性。 LSC 或其后代白血病祖细胞 (LPC) 在某个阶段可能会发生额外的基因变化，导致白血病进一步转变为更晚期的急变期 (CML-BP)，这种情况对治疗反应不佳，通常是致命的。我们假设对 TKI 耐药或耐药的 LSC 和/或 LPC 可能是“定时炸弹”，积累额外的遗传畸变，并最终“爆炸”产生额外的 TKI 耐药克隆和具有复杂核型的 CML-BP 克隆。
BCR-ABL1 kinase-induced chronic myeloid leukemia in chronic phase (CML-CP) usually responds to treatment with ABL tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib and nilotinib. In most patients TKIs reduce the leukemia cell load substantially, but some leukemia cells, for example leukemia stem cells (LSCs) are intrinsically refractory to TKIs. In addition, some patients who respond initially may later become resistant to TKIs due to accumulation of point mutations in BCR-ABL1 kinase. LSCs or their progeny, leukemia progenitor cells (LPCs), at some stage may acquire additional genetic changes that cause the leukemia to transform further to a more advanced blast phase (CML-BP), which responds poorly to treatment and is usually fatal. We postulate that LSCs and/or LPCs refractory or resistant to TKIs may be “ticking time-bombs” accumulating additional genetic aberrations and eventually “exploding” to generate additional TKI-resistant clones and CML-BP clones with complex karyotypes.