Expression of a Src Family Kinase in Chronic Myelogenous Leukemia Cells Induces Resistance to Imatinib in a Kinase-dependent Manner
Expression of a Src Family Kinase in Chronic Myelogenous Leukemia Cells Induces Resistance to Imatinib in a Kinase-dependent Manner
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DOI：
10.1074/jbc.m109.090043
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发表时间：
2010-07-09
影响因子：
4.8
通讯作者：
Smithgall, Thomas E.
中科院分区：
文献类型：
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作者：
Pene-Dumitrescu, Teodora;Smithgall, Thomas E.
Bcr-Abl激酶抑制剂伊马替尼在慢性粒细胞白血病（CML）中非常有效，尽管耐药性是一个新出现的问题。髓样Src家族激酶如Hck和林恩通常在缺乏Bcr-Abl突变的伊马替尼耐药CML细胞中过表达。在这里，我们测试了Hck过表达是否足以诱导伊马替尼耐药，使用野生型Hck和突变体（Hck-T338 A），是唯一敏感的吡唑并嘧啶抑制剂，NaPP 1。K562 CML细胞中任一激酶的表达导致对伊马替尼诱导的凋亡的抵抗和软琼脂集落形成的抑制。用NaPP 1治疗恢复了表达T338 A但不表达野生型Hck的细胞对伊马替尼的敏感性，表明抗性需要Hck激酶活性。NaPP 1还减少了Hck介导的Bcr-Abl磷酸化位点，这些位点可能仅在表达Hck-T338 A的细胞中影响伊马替尼敏感性。这些数据表明，Src家族激酶活性升高足以通过可能涉及Bcr-Abl磷酸化的机制诱导伊马替尼耐药。
The Bcr-Abl kinase inhibitor imatinib is remarkably effective in chronic myelogenous leukemia (CML), although drug resistance is an emerging problem. Myeloid Src family kinases such as Hck and Lyn are often overexpressed in imatinib-resistant CML cells that lack Bcr-Abl mutations. Here we tested whether Hck overexpression is sufficient to induce imatinib resistance using both wild-type Hck and a mutant (Hck-T338A) that is uniquely sensitive to the pyrazolo-pyrimidine inhibitor, NaPP1. Expression of either kinase in K562 CML cells caused resistance to imatinib-induced apoptosis and inhibition of soft-agar colony formation. Treatment with NaPP1 restored sensitivity to imatinib in cells expressing T338A but not wild-type Hck, demonstrating that resistance requires Hck kinase activity. NaPP1 also reduced Hck-mediated phosphorylation of Bcr-Abl at sites that may affect imatinib sensitivity exclusively in cells expressing Hck-T338A. These data show that elevated Src family kinase activity is sufficient to induce imatinib resistance through a mechanism that may involve phosphorylation of Bcr-Abl.