Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBPalpha.

Abstract

Chronic phase-to-blast crisis transition in chronic myelogenous leukemia (CML) is associated with differentiation arrest and down-regulation of C/EBPalpha, 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 (STI571) because of mutations in the kinase domain that interfere with drug binding. We show here that the restoration of C/EBPalpha activity in STI571-sensitive or -resistant 32D-BCR/ABL cells induced granulocyte differentiation, inhibited proliferation in vitro and in mice, and suppressed leukemogenesis. Moreover, activation of C/EBPalpha eradicated leukemia in 4 of 10 and in 6 of 7 mice injected with STI571-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/EBPalpha, which were more potent than those of K298E C/EBPalpha, a mutant defective in DNA binding and transcription activation that failed to induce granulocyte differentiation. Activation of C/EBPalpha in blast cells from 4 patients with CML-BC, including one resistant to STI571 and BMS-354825 and carrying the T315I Abl kinase domain mutation, also induced granulocyte differentiation. Thus, these data indicate that C/EBPalpha has potent antileukemia effects even in cells resistant to ATP-binding competitive tyrosine kinase inhibitors, and they portend the development of anti-leukemia therapies that rely on C/EBPalpha activation.

• Authors: Giovanna Ferrari-Amorotti, Karen Keeshan, Michela Zattoni, Clara Guerzoni, Giorgio Iotti, Sara Cattelani, Nick J Donato, Bruno Calabretta
• Journal: Blood (Blood) Vol. 108 Issue 4 Pg. 1353-62 (Aug 15 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16670262 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• CCAAT-Enhancer-Binding Protein-alpha
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• Thiazoles
• Imatinib Mesylate
• Fusion Proteins, bcr-abl
• Dasatinib

Topics

• Animals
• Benzamides
• Blast Crisis (drug therapy, genetics, metabolism)
• CCAAT-Enhancer-Binding Protein-alpha (biosynthesis, genetics)
• Cell Differentiation (drug effects, genetics)
• Cell Proliferation (drug effects)
• Dasatinib
• Drug Resistance, Neoplasm (drug effects, genetics)
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics, metabolism)
• Granulocytes (metabolism)
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism)
• Mice
• Mutation
• Piperazines (metabolism, pharmacology)
• Protein Binding (drug effects, genetics)
• Protein Kinase Inhibitors (metabolism, pharmacology)
• Pyrimidines (metabolism, pharmacology)
• Thiazoles (metabolism, pharmacology)