RAC2, AEP, and ICAM1 expression are associated with CNS disease in a mouse model of pre-B childhood acute lymphoblastic leukemia.
Authors
Holland, MarkCastro, 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
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
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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 BloodJournal
BloodDOI
10.1182/blood-2010-09-307330PubMed ID
21606482Type
ArticleLanguage
enISSN
1528-0020ae974a485f413a2113503eed53cd6c53
10.1182/blood-2010-09-307330
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