Activation of mTORC1 Signaling Pathway in AIDS-Related Lymphomas (ARL)
M El-Salem, PN Raghunath, M Marzec, M Kasprzycka, X Liu, MA Wasik. University of Pennsylvania, Philadelphia, PA
Background: ARL typically represent the proliferation of enlarged, transformed B lymphocytes from the category of diffuse large cell lymphoma (DLBCL), Burkitt lymphoma (BL), and Hodgkin lymphoma (HL). The pathogenesis of ARL is poorly understood and treatment results unsatisfactory. mTOR serine/threonine kinase is involved in key cellular functions including protein synthesis and proliferation. mTOR associates with several proteins including raptor to form the mTORC1 complex which activates p70S6 kinase 1 (p70S6K1) and inhibits 4E binding protein 1 (4E-BP1). In turn, p70S6K1 phosphorylates an S6 protein (S6rp). The highly potent and specific inhibitors from the rapamycin family can functionally inactivate mTORC1.
Design: By immunohistochemistry with antibodies against the phospho-serines in S6rp and 4EBP1 proteins, we examined tissues from 29 ARL cases and 8 HIV-associated lymphadenopathy (HAL) cases. In addition, we evaluated by Western blotting 6 cell lines developed from DLBCL and BL as well as by infection with Epstein-Barr virus (EBV) for activation of the mTORC1 pathway before and after exposure to inhibitors of mTORC1 and Syk kinase.
Results: mTORC1 pathway activation was identified in all ARL cases regardless of their histologic classification. TORC1 was also activated in the hyperplastic but not in the involuted follicles of the HIV-associated lymphadenopathy, supporting the notion that mTORC1 activation is a common feature of transformed lymphocytes irrespective of their reactive or malignant phenotype. Finally, we found that inhibition of not only mTORC1 but also Syk kinase resulted in at least partial suppression of the mTORC1 activation in all types of the analyzed cell lines.
Conclusions: These findings indicate that ARL universally display constitutive activation of the mTORC1 signaling pathway as demonstrated in situ in ARL tissues using antibodies specific for serine phosphorylated mTOR target proteins. Furthermore, ARL and possibly other lymphomas derived from transformed lymphocytes represent a potential therapeutic target for mTORC1 inhibitors as well as inhibitors of its upstream activators including Syk kinase.
Activation of mTORC1 signaling pathway in ARL, DLBCL type.
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 170, Wednesday Morning