T-Lymphoblastic Lymphoma Cells Express High Levels of BCL2, S1P1, and ICAM1, Leading to a Blockade of Tumor Cell Intravasation

Abstract

Summary 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 to 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.

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

“…Considering the crucial role had by aberrantly activated Akt in the pathogenesis of T-ALL, 16,17 we studied the efficacy of MK-2206, a novel allosteric Akt inhibitor, 19 as a potential therapeutic agent. MK-2206 decreased the viability of T-ALL cell lines, in a concentration-dependent manner.…”

“…16 Of note, the evolution of T-cell lymphoma to T-ALL was dependent, among other molecular alterations, also on Akt hyperactivation. 17 Hence, there is a strong rationale for developing novel, molecularly targeted therapies against Akt in T-ALL.…”

Zebrafish second heart field development relies on progenitor specification in anterior lateral plate mesoderm and nkx2.5 function

“…Primers F1, R1 and R2 (Targoff et al, 2008) were used to amplify first-strand cDNAs for unspliced (F1/R1) or spliced (F1/R2) nkx2.5 transcripts. Amplification of the 18S rRNA (Feng et al, 2010) was used as a loading control.…”

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

“…14,15 Moreover, recent findings in a zebrafish model, have highlighted that the transition from T-lymphoblastic lymphoma to T-ALL was characterized by increased phosphorylation levels of Akt. 16 The allosteric inhibition of mTORC1 by rapamycin has only modest effects on T-ALL cells. 17 This could be because, among other things, of the fact that rapamycin is mainly cytostatic and does not dephosphorylate the translational repressor 4E-BP1 in preclinical models of T-ALL.…”