In the last few years, our studies of mantle cell lymphoma (MCL) have been focused on developing a cellular signaling map of this lymphoms to better understand the factors driving cell growth, and to identify potential therapeutic targets and prognostic markers. As a first approach, we initiated studies investigating the potential significance of important cellular kinases known to be involved in proliferation and survival pathways in cell line models as well as in primary samples. We recently published studies showing that aggressive (blastoid) MCL differs from typical MCL as a result of PI3K/AKT pathway activation (Blood, 2006). Cell lines that simulate blastoid MCL and primary blastoid MCL cases show phosphorylation of multiple downstream AKT targets, while typical MCL do not. We are pursuing studies to identify the mechanism by which AKT is activated by assessing components upstream of AKT, including PI3K signaling components and the B-cell receptor (BCR) signaling pathway. Our most recent data indicates that signaling through the BCR-associated SYK kinase is necessary for activation of AKT to occur. Furthermore, we demonstrate that combinations of drugs that target both the PI3K/AKT pathway and the B-cell receptor (BCR) signaling pathway have synergistic activity against MCL, suggesting a therapeutic approach. We are currently preparing two manuscripts to report these data. In a related study focused on MCL therapy (Clinical Cancer Research, in press), we have shown that Nutlin-3, a small molecular inhibitor of the ubiquitin-ligase MDM2, is highly effective in inducing cell death in MCL with wild-type TP53 and also has activity in MCL with mutant TP53. We also provide data concerning the mechanism of activity of Nutlin-3 in both wild-type TP53 and mutant TP-53 bearing MCL cells. Furthermore, we show that the combination of Nutlin-3 with the proteasome inhibitor Bortezomib results in synergistic cytotoxicity in MCL cells harboring either wild-type or mutant TP53. These results provide a basis for the rational use of Nutlin-3 in MCL either alone or in combination with other compounds known to have activity in MCL. We are also continuing to work with Dr. Leticia Quintanilla-Martinez (Tuebingin, Germany), a former fellow in my laboraory, on the role of Cyclin D1 in mantle cell lymphomagenesis. In these studies we have shown that Cyclin D1 is not necessary for mantle cell lymphoma survival (Leukemia 2008). Furthermore through the use of si-RNA targeting Cyclin D1, we demonstrate the existence of a compensatory feedback loop with Cyclin D2 that allows cells to continue growing following Cyclin D1 knockdown. These studies, initiated in our laboratory several years ago, are now primarily being performed in Dr. Quintanilla-Martinez's laboratory. In anaplastic large cell lymphoma (ALCL), we have focused on uncovering the signaling links between the abnormally activated ALK kinase and the development of the lymphoma through a series of targeted inhibition experiments, combined with expression analysis. We recently showed that the abnormally expressed ALK kinase results in the activation of the C/EBP beta transcription factor, which had not previously been shown to be expressed in ALCL (Blood. 2006). We also found that the LIP isoform was preferentially expressed in ALCL, which also occurs in other aggressive cancers. Our current studies indicate that C/EBP beta is critical for ALCL cell growth, and that its activation occurs through two independent convergent pathways activated by the ALK kinase (manuscript under review). Other investigators have reported that ALK activates STAT3, and that STAT3 is necessary for ALCL survival. Our study indicates that STAT3 is required for C/EBP beta gene expression, suggesting that at least one of the critical STAT3 targets is C/EBP beta. Biological activity of C/EBP beta also requires critical phosphoylation events, and our studies indicate that MAPK activation by ALK is also necessary for C/EBP beta activity. This is an unusual example of a proximal oncogenic event activating a downstream target through two convergent pathways, one acting at the transcriptional level (STAT3) and the second, at the post-transcriptional level (MAPK). Studies are ongoing in collaboration with Dr. Leticia Quintanilla-Martinez to identify genes controlled by C/EBP beta using targeted knockdown experiments, combined with expression analysis.
| Killian, J Keith; Bilke, Sven; Davis, Sean et al. (2009) Large-scale profiling of archival lymph nodes reveals pervasive remodeling of the follicular lymphoma methylome. Cancer Res 69:758-64 |
| Wang, Yun; Digiovanna, John J; Stern, Jere B et al. (2009) Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas. Proc Natl Acad Sci U S A 106:6279-84 |
| Tabe, Yoko; Sebasigari, Denise; Jin, Linhua et al. (2009) MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma. Clin Cancer Res 15:933-42 |
