The Journal of Experimental Medicine
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Published online 30 January 2006 doi:10.1084/jem.20052242
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 2, 371-381
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ARTICLE

 Block of C/EBP{alpha} function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations

Hanna S. Radomska1, Daniela S. Bassères1, Rui Zheng3, Pu Zhang1, Tajhal Dayaram1, Yukiya Yamamoto1, David W. Sternberg2, Nathalie Lokker4, Neill A. Giese4, Stefan K. Bohlander5,6, Susanne Schnittger5, Marie-Hélène Delmotte7, Roger J. Davis7, Donald Small2, Wolfgang Hiddemann5,6, D. Gary Gilliland2, and Daniel G. Tenen1

1 Beth Israel Deaconess Medical Center/Harvard Medical School and 2 Howard Hughes Medical Institute/Brigham and Women's Hospital, Boston, MA 02115
3 Johns Hopkins University School of Medicine, Baltimore, MD 21231
4 Millennium Pharmaceuticals, Inc., San Francisco, CA 94080
5 Laboratory of Leukemia Diagnostics, Department of Internal Medicine III and 6 CCG Acute Leukemias, GSF National Research Center of Environment and Health, D-81377 Munich, Germany
7 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655

CORRESPONDENCE Daniel G. Tenen: dtenen{at}bidmc.harvard.edu

Mutations constitutively activating FLT3 kinase are detected in ~30% of acute myelogenous leukemia (AML) patients and affect downstream pathways such as extracellular signal–regulated kinase (ERK)1/2. We found that activation of FLT3 in human AML inhibits CCAAT/enhancer binding protein {alpha} (C/EBP{alpha}) function by ERK1/2-mediated phosphorylation, which may explain the differentiation block of leukemic blasts. In MV4;11 cells, pharmacological inhibition of either FLT3 or MEK1 leads to granulocytic differentiation. Differentiation of MV4;11 cells was also observed when C/EBP{alpha} mutated at serine 21 to alanine (S21A) was stably expressed. In contrast, there was no effect when serine 21 was mutated to aspartate (S21D), which mimics phosphorylation of C/EBP{alpha}. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBP{alpha} may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies.

H.S. Radomska and D.S. Bassères contributed equally to this work.

Abbreviations used: AML, acute myelogenous leukemia; C/EBP{alpha}, CCAAT/enhancer binding protein {alpha}; ER, estrogen receptor; ERK, extracellular signal–regulated kinase; ITD, internal tandem duplication; MAP, mitogen-activated protein; NBT, Nitro blue tetrazolium; PDGFR, platelet-derived growth factor receptor.


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