The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20071875
The Journal of Experimental Medicine, Vol. 205, No. 3, 515-522
The Rockefeller University Press, 0022-1007 $30.00
© Petropoulos et al.
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BRIEF DEFINITIVE REPORT

 A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis

Konstantin Petropoulos1,2, Natalia Arseni1,2, Christina Schessl1,2, Christiane R. Stadler1,2, Vijay P.S. Rawat1,2, Aniruddha J. Deshpande1,2, Bernhard Heilmeier1,2, Wolfgang Hiddemann1,2, Leticia Quintanilla-Martinez3, Stefan K. Bohlander1,2, Michaela Feuring-Buske1,2, and Christian Buske1,2

1 Department of Medicine III, Klinikum Grosshadern, D-81377 Munich, Germany
2 Clinical Cooperative Group Leukemia and 3 Institute of Pathology, Helmholtz Zentrum Munich, D-81377 Munich, Germany

CORRESPONDENCE Christian Buske: buske{at}helmholtz-muenchen.de

Canonical Wnt signaling is critically involved in normal hematopoietic development and the self-renewal process of hematopoietic stem cells (HSCs). Deregulation of this pathway has been linked to a large variety of cancers, including different subtypes of leukemia. Lef-1 is a major transcription factor of this pathway and plays a pivotal role in lymphoid differentiation as well as in granulopoiesis. Here, we demonstrate Lef-1 expression in murine HSCs as well as its expression in human leukemia. Mice transplanted with bone marrow retrovirally transduced to express Lef-1 or a constitutive active Lef-1 mutant showed a severe disturbance of normal hematopoietic differentiation and finally developed B lymphoblastic and acute myeloid leukemia (AML). Lef-1–induced AMLs were characterized by immunoglobulin (Ig) DH-JH rearrangements and a promiscuous expression of lymphoid and myeloid regulatory factors. Furthermore, single cell experiments and limiting dilution transplantation assays demonstrated that Lef-1–induced AML was propagated by a leukemic stem cell with lymphoid characteristics displaying Ig DH-JH rearrangements and a B220+ myeloid marker– immunophenotype. These data indicate a thus far unknown role of Lef-1 in the biology of acute leukemia, pointing to the necessity of balanced Lef-1 expression for an ordered hematopoietic development.


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