Leukemogenesis induced by wild-type and ST157 1-resistant BCR/ABL is potently suppressed by C/EBPα

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.