T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation.
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.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Hui
H
Feng
David L
DL
Stachura
Richard M
RM
White
Alejandro
A
Gutierrez
Lu
L
Zhang
Takaomi
T
Sanda
Cicely A
CA
Jette
Joseph R
JR
Testa
Donna S
DS
Neuberg
David M
DM
Langenau
Jeffery L
JL
Kutok
Leonard I
LI
Zon
David
D
Traver
Mark D
MD
Fleming
John P
JP
Kanki
A Thomas
AT
Look
D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy; D001808:Blood Vessels / Q000201:enzymology / Q000473:pathology*; D002449:Cell Aggregation; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D004789:Enzyme Activation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D049349:Receptors, Lysosphingolipid; D018799:Intercellular Adhesion Molecule-1; D051057:Proto-Oncogene Proteins c-akt