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    RAC2, AEP, and ICAM1 expression are associated with CNS disease in a mouse model of pre-B childhood acute lymphoblastic leukemia.

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    Authors
    Holland, Mark
    Castro, Fernanda V
    Alexander, Seema
    Smith, Duncan L
    Liu, Jizhong
    Walker, Michael G
    Bitton, Danny A
    Mulryan, Kate
    Ashton, Garry
    Blaylock, Morgan
    Bagley, Steven
    Connolly, Yvonne
    Bridgeman, John S
    Miller, Crispin J
    Krishnan, Shekhar
    Dempsey, Clare E
    Masurekar, Ashish
    Stern, Peter L
    Whetton, Anthony D
    Saha, Vaskar
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    Affiliation
    Cancer Research UK Children's Cancer Group, Manchester Academic Health Science Centre, School of Cancer & Enabling Sciences, University of Manchester, Manchester, United Kingdom.
    Issue Date
    2011-07-21
    
    Metadata
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    Abstract
    We developed a murine model of CNS disease to obtain a better understanding of the pathogenesis of CNS involvement in pre-B-cell acute lymphoblastic leukemia (ALL). Semiquantitative proteomic discovery-based approaches identified unique expression of asparaginyl endopeptidase (AEP), intercellular adhesion molecule 1 (ICAM1), and ras-related C3 botulinum toxin substrate 2 (RAC2), among others, in an invasive pre-B-cell line that produced CNS leukemia in NOD-SCID mice. Targeting RAC2 significantly inhibited in vitro invasion and delayed disease onset in mice. Induced expression of RAC2 in cell lines with low/absent expression of AEP and ICAM1 did not result in an invasive phenotype or murine CNS disease. Flow cytometric analysis identified an enriched population of blast cells expressing ICAM1/lymphocyte function associated antigen-1 (LFA-1)/CD70 in the CD10(+)/CD19(+) fraction of bone marrow aspirates obtained from relapsed compared with normal controls and those with primary disease. CD10(+)/CD19(+) fractions obtained from relapsed patients also express RAC2 and give rise to CNS disease in mice. Our data suggest that combinations of processes are involved in the pathogenesis of CNS disease in pre-B-cell ALL, support a model in which CNS disease occurs as a result of external invasion, and suggest that targeting the processes of adhesion and invasion unique to pre-B cells may prevent recurrences within the CNS.
    Citation
    RAC2, AEP, and ICAM1 expression are associated with CNS disease in a mouse model of pre-B childhood acute lymphoblastic leukemia. 2011, 118 (3):638-49 Blood
    Journal
    Blood
    URI
    http://hdl.handle.net/10541/146617
    DOI
    10.1182/blood-2010-09-307330
    PubMed ID
    21606482
    Type
    Article
    Language
    en
    ISSN
    1528-0020
    ae974a485f413a2113503eed53cd6c53
    10.1182/blood-2010-09-307330
    Scopus Count
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    All Paterson Institute for Cancer Research

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