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PMID: 16670262 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Blood ·Vol. 108 ·No. 4 ·2006-08-15 ·Pages 1353-62

Ferrari-Amorotti G, Keeshan K, Zattoni M, Guerzoni C, Iotti G, Cattelani S, Donato NJ, Calabretta B

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.

MeSH Terms
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
Chemicals
Benzamides CCAAT-Enhancer-Binding Protein-alpha Piperazines Protein Kinase Inhibitors Pyrimidines Thiazoles Imatinib Mesylate Fusion Proteins, bcr-abl Dasatinib
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Ferrari-Amorotti Giovanna
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA 19107, USA.
Keeshan Karen
Zattoni Michela
Guerzoni Clara
Iotti Giorgio
Cattelani Sara
Donato Nick J
Calabretta Bruno
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2006-01-011833
Published
2006-08-15
Epub
2006-00-02
Pages
1353-62
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895881
Subset
IM
Grants
NCI NIH HHS · CA 95111 · United States
PHS HHS · P01 78890 · United States
External Links
PubMed source DOI: 10.1182/blood-2006-01-011833 PMC Full Text View journal details
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