Published online
doi:10.1084/jem.20090004
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© Trageser et al.
Pre–B cell receptor–mediated cell cycle arrest in Philadelphia chromosome–positive acute lymphoblastic leukemia requires IKAROS function
Daniel Trageser1,2,
Ilaria Iacobucci3,
Rahul Nahar1,
Cihangir Duy1,2,
Gregor von Levetzow1,2,
Lars Klemm1,2,
Eugene Park1,
Wolfgang Schuh4,
Tanja Gruber1,
Sebastian Herzog5,
Yong-mi Kim1,
Wolf-Karsten Hofmann6,
Aihong Li7,
Clelia Tiziana Storlazzi8,
Hans-Martin Jäck4,
John Groffen1,
Giovanni Martinelli3,
Nora Heisterkamp1,
Hassan Jumaa5, and
Markus Müschen1,2
1 Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027
2 Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
3 Department of Hematology/Oncology "L. and A. Seràgnoli," University of Bologna, 40138 Bologna, Italy
4 Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen, 91054 Erlangen, Germany
5 Max-Planck Institute for Immunobiology, D-79108 Freiburg, Germany
6 Department of Hematology and Oncology, University Hospital Mannheim, 68167 Mannheim, Germany
7 Department of Medical Biosciences, Pathology, Umea University, 90187 Umea, Sweden
8 Department of Genetics and Microbiology, University of Bari, 70126 Bari, Italy
CORRESPONDENCE Markus Müschen: mmuschen{at}chla.usc.edu
B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre–B cell receptor–dependent stages. The Philadelphia chromosome–positive (Ph+) subtype of ALL accounts for 25–30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre–B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph+ ALL cells. Pre–B cell receptor–mediated cell cycle arrest in Ph+ ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre–B cell receptor signaling pathway, even if expression of the pre–B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre–B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph+ ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre–B cell receptor–mediated tumor suppression.
Abbreviations used: ALL, acute lymphoblastic leukemia; DN, dominant-negative; IGHM, Ig µ heavy chain; mRNA, messenger RNA; Ph, Philadelphia chromosome; Tet, tetracycline; tTA, Tet-controlled transactivatore.
© 2009 Trageser et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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