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Feng H , Stachura DL , White RM , Gutierrez A , Zhang L , Sanda T , Jette CA , Testa JR , Neuberg DS , Langenau DM , Kutok JL , Zon LI , Traver D , Fleming MD , Kanki JP , Look AT
T-Lymphoblastic Lymphoma Cells Express High Levels of BCL2, S1P1, and ICAM1, Leading to a Blockade of Tumor Cell Intravasation
Cancer Cell. 2010 Oct;18(4) :353-366
AbstractThe 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.
NotesFeng, Hui Stachura, David L. White, Richard M. Gutierrez, Alejandro Zhang, Lu Sanda, Takaomi Jette, Cicely A. Testa, Joseph R. Neuberg, Donna S. Langenau, David M. Kutok, Jeffery L. Zon, Leonard I. Traver, David Fleming, Mark D. Kanki, John P. Look, A. Thomas National Institutes of Health [CA068484, K99CA134743, NRSA T32-HL086344, 1K08CA133103, 1K01DK074555, CA077429, K01AR05562190-01A1, 3K01AR055619-03S1]; Leukemia & Lymphoma Society ; Prevent Cancer Foundation ; William Lawrence Foundation ; Harvard Stem Cell Institute We thank M. Calicchio, Drs. L. Cameron, E. Payne, E. Breen, J. Struthers, G. Wei for technical help, advice, and reagents, J. Gilbert for editorial advice, and B. Baker and R. Gilbert and K.P. Kotredes for fish care and husbandry. This work was supported by grants from the National Institutes of Health (CA068484, A.T.L; K99CA134743, H.F.; NRSA T32-HL086344, D.L.S.; 1K08CA133103, A.G.; 1K01DK074555, C.A.J.; CA077429, J.R.T.; K01AR05562190-01A1 and 3K01AR055619-03S1, D.M.L.), the Leukemia & Lymphoma Society (H.F.), Prevent Cancer Foundation Postdoctoral Fellowship (D.L.S.), the William Lawrence Foundation (A.G.), and a Seed Grant from the Harvard Stem Cell Institute (D.M.L). L.I.Z. is a founder and stockholder of Fate, Inc. and a scientific advisor for Stemgent. A.T.L. is on the board of iLAB and a scientific advisor for OncoMed, Inc. The content of this research is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 43 Cell press; 600 technology square, 5th floor, cambridge, ma 02139 usa 673xj