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Pre-B cell receptor...
Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function
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- Trageser, Daniel (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- Iacobucci, Ilaria (author)
- Department of Hematology/Oncology “L. and A. Seràgnoli,” University of Bologna, Italia
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- Nahar, Rahul (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- Duy, Cihangir (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- von Levetzow, Gregor (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- Klemm, Lars (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- Park, Eugene (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- Schuh, Wolfgang (author)
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen, Germany
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- Gruber, Tanja (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- Herzog, Sebastian (author)
- Max-Planck Institute for Immunobiology, D-79108 Freiburg, Germany
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- Kim, Yong-mi (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- Hofmann, Wolf-Karsten (author)
- Department of Hematology and Oncology, University Hospital Mannheim, Germany
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- Li, Aihong (author)
- Umeå universitet,Klinisk kemi
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- Storlazzi, Clelia Tiziana (author)
- Department of Genetics and Microbiology, University of Bari, Italy
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- Jäck, Hans-Martin (author)
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen, Germany
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- Groffen, John (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- Martinelli, Giovanni (author)
- Department of Hematology/Oncology “L. and A. Seràgnoli,” University of Bologna, Italy
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- Heisterkamp, Nora (author)
- Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
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- Jumaa, Hassan (author)
- Max-Planck Institute for Immunobiology, D-79108 Freiburg, Germany
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- Müschen, Markus (author)
- 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
- English.
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 206:8, s. 1739-1753
- Related links:
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http://jem.rupress.o...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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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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- By the author/editor
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Trageser, Daniel
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Iacobucci, Ilari ...
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Nahar, Rahul
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Duy, Cihangir
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von Levetzow, Gr ...
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Klemm, Lars
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Park, Eugene
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Schuh, Wolfgang
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Gruber, Tanja
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Herzog, Sebastia ...
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Kim, Yong-mi
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Hofmann, Wolf-Ka ...
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Li, Aihong
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Storlazzi, Cleli ...
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Jäck, Hans-Marti ...
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Groffen, John
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Martinelli, Giov ...
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Heisterkamp, Nor ...
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Jumaa, Hassan
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Müschen, Markus
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Journal of Exper ...
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Umeå University