Leukemogenesis induced by wild-type and ST157 1-resistant BCR/ABL is potently suppressed by C/EBPα
Leukemogenesis induced by wild-type and ST157 1-resistant BCR/ABL is potently suppressed by C/EBPα
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DOI：
10.1182/blood-2006-01-011833
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发表时间：
2006-08-15
期刊：
影响因子：
20.3
通讯作者：
Calabretta, Bruno
中科院分区：
文献类型：
--
作者：
Ferrari-Amorotti, Giovanna;Keeshan, Karen;Calabretta, Bruno
慢性粒细胞白血病（CML）的慢性期向急变期转变与分化停滞和C/EBP α（粒细胞分化所必需的转录因子）的下调有关。CML急变期（CML-BC）患者对断点簇区-Abelson小鼠白血病（BCR/ABL）激酶抑制剂伊马替尼（ST 1571）治疗迅速产生耐药性，因为激酶结构域的突变干扰了药物结合。我们发现，在ST 1571敏感或耐药的32 D-BCR/ABL细胞中，C/EBP α活性的恢复诱导粒细胞分化，抑制体外和小鼠的增殖，并抑制白血病发生。此外，激活C/EBPa根除白血病在4/10和6/7小鼠注射ST 1571敏感或耐药32 D-BCR/ABL细胞，分别。分化诱导和增殖抑制是白血病发生的最佳抑制所必需的，如p42 C/EBP α的作用所示，其比K298 E C/EBP α的作用更有效，K298 E C/EBP α是DNA结合和转录激活缺陷的突变体，其未能诱导粒细胞分化。来自4名CML-BC患者的原始细胞中C/EBP α的激活也诱导粒细胞分化，其中包括对ST 1571和BMS-354825耐药并携带T3151 Abl激酶结构域突变的患者。因此，这些数据表明，C/EBP α即使在对ATP结合竞争性酪氨酸激酶抑制剂具有抗性的细胞中也具有有效的抗白血病作用，并且它们预示着依赖于C/EBP α活化的抗白血病疗法的发展。
Chronic phase-to-blast crisis transition in chronic myelogenous leukemia (CML) is associated with differentiation arrest and down-regulation of C/EBP alpha, a transcription factor essential for granulocyte differentiation. Patients with CML in blast crisis (CML-BC) became rapidly resistant to therapy with the breakpoint cluster region-Abelson murine leukemia (BCR/ABL) kinase inhibitor imatinib (ST1571) because of mutations in the kinase domain that interfere with drug binding. We show here that the restoration of C/EBP alpha activity in ST1571-sensitive or -resistant 32D-BCR/ABL cells induced granulocyte differentiation, inhibited proliferation in vitro and in mice, and suppressed leukemogenesis. Moreover, activation of C/EBPa eradicated leukemia in 4 of 10 and in 6 of 7 mice injected with ST1571-sensitive or -resistant 32D-BCR/ABL cells, respectively. Differentiation induction and proliferation inhibition were required for optimal suppression of leukemogenesis, as indicated by the effects of p42 C/EBP alpha, which were more potent than those of K298E C/EBP alpha, a mutant defective in DNA binding and transcription activation that failed to induce granulocyte differentiation. Activation of C/EBP alpha in blast cells from 4 patients with CML-BC, including one resistant to ST1571 and BMS-354825 and carrying the T3151 Abl kinase domain mutation, also induced granulocyte differentiation. Thus, these data indicate that C/EBP(x has potent antileukemia effects even in cells resistant to ATP-binding competitive tyrosine kinase inhibitors, and they portend the development of antileukemia therapies that rely on C/EBP alpha activation.