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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1353-1362.
Prepublished online as a Blood First Edition Paper on May 2, 2006; DOI 10.1182/blood-2006-01-011833.
 Previous Article | Next Article 
Submitted January 5, 2006
Accepted April 10, 2006
Leukemogenesis induced by wild type and STI571-resistant
BCR/ABL
is potently suppressed by C/EBP
Giovanna Ferrari Amorotti, Karen Keeshan, Michela Zattoni, Clara Guerzoni, Giorgio Iotti, Sara Cattelani, Nick J Donato, and Bruno Calabretta*
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University
Department of Pathology, Institute for Medicine and Engineering, University of Pennsylvania
Department of Bioimmunotherapy, University of Texas, M.D. Anderson Cancer Center
1Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College
* Corresponding author; email: b_calabretta{at}lac.jci.tju.edu.
Chronic phase-to-blast crisis transition in chronic
myelogenous leukemia is associated with differentiation
arrest and downregulation of C/EBP , a
transcription factor essential for granulocytic
differentiation.
CML-blast crisis patients became rapidly
resistant to therapy with the BCR/ABL kinase inhibitor
Imatinib (Gleevec; STI571) because of mutations in the
kinase domain interfering with drug ¡ s binding.
We show here that restoration of C/EBP activity
in STI571-sensitive or -resistant 32D-BCR/ABL cells
induced granulocytic differentiation, inhibited
proliferation in vitro and in mice, and suppressed
leukemogenesis. Moreover, activation of C/EBP
eradicated leukemia in 4 of 10 and 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 more potent effect of p42 C/EBP, than K298E C/EBP, a mutant defective in
DNA binding and transcription activation which fails to
induce granulocytic differentiation.
Activation of C/EBP in blast cells from four CML-
BC patients including one resistant to STI571 and BMS-
354825 and carrying the T315I Abl kinase domain mutation
also induced granulocytic differentiation. Thus, these
data indicate that C/EBP has potent anti-
leukemia effects even in cells resistant to ATP-binding
competitive tyrosine kinase inhibitors and portend to
the development of anti-leukemia therapies relying on
C/EBP activation.
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