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Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function

Trageser, Daniel (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
Iacobucci, Ilaria (författare)
Department of Hematology/Oncology “L. and A. Seràgnoli,” University of Bologna, Italia
Nahar, Rahul (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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Duy, Cihangir (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
von Levetzow, Gregor (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
Klemm, Lars (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
Park, Eugene (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
Schuh, Wolfgang (författare)
Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen, Germany
Gruber, Tanja (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
Herzog, Sebastian (författare)
Max-Planck Institute for Immunobiology, D-79108 Freiburg, Germany
Kim, Yong-mi (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
Hofmann, Wolf-Karsten (författare)
Department of Hematology and Oncology, University Hospital Mannheim, Germany
Li, Aihong (författare)
Umeå universitet,Klinisk kemi
Storlazzi, Clelia Tiziana (författare)
Department of Genetics and Microbiology, University of Bari, Italy
Jäck, Hans-Martin (författare)
Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen, Germany
Groffen, John (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
Martinelli, Giovanni (författare)
Department of Hematology/Oncology “L. and A. Seràgnoli,” University of Bologna, Italy
Heisterkamp, Nora (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
Jumaa, Hassan (författare)
Max-Planck Institute for Immunobiology, D-79108 Freiburg, Germany
Müschen, Markus (författare)
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles Department of Hematology/Oncology “L and A. Seràgnoli,” University of Bologna, Italia (creator_code:org_t)
2009-07-20
2009
Engelska.
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 206:8, s. 1739-1753
Relaterad länk:
http://jem.rupress.o...
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https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.

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