Abstract
The molecular events underlying the progression of T-lymphoblastic lymphoma (T-LBL) to acute T-lymphoblastic leukemia (T-ALL) remain elusive. In our zebrafish model, concomitant overexpression of bcl-2 with Myc accelerated T-LBL onset while inhibiting progression to T-ALL. The T-LBL cells failed to invade the vasculature and showed evidence of increased homotypic cell-cell adhesion and autophagy. Further analysis using clinical biopsy specimens revealed autophagy and increased levels of BCL2, S1P1, and ICAM1 in human T-LBL compared with T-ALL. Inhibition of S1P1 signaling in T-LBL cells led to decreased homotypic adhesion in vitro and increased tumor cell intravasation in vivo. Thus, blockade of intravasation and hematologic dissemination in T-LBL is due to elevated S1P1 signaling, increased expression of ICAM1, and augmented homotypic cell-cell adhesion.
Copyright © 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Autophagy
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Blood Vessels / enzymology
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Blood Vessels / pathology*
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Cell Aggregation
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Cell Line, Tumor
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Cell Movement
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Disease Progression
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Enzyme Activation
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Gene Expression Regulation, Leukemic
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Humans
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Immunohistochemistry
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / enzymology
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Proto-Oncogene Proteins c-myc / metabolism
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Receptors, Lysosphingolipid / antagonists & inhibitors
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Receptors, Lysosphingolipid / genetics
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Receptors, Lysosphingolipid / metabolism*
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Zebrafish
Substances
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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Receptors, Lysosphingolipid
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Intercellular Adhesion Molecule-1
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Proto-Oncogene Proteins c-akt