Using immunohistochem. with antibodies against the phosphoserine residues in both S6rp and 4E binding protein 1, we identified the activation of the mammalian target of rapamycin (mTORC)1 pathway in 29 cases of AIDS-related lymphoma. These cases represented a diverse spectrum of histol. types of non-Hodgkin lymphoma (24 cases) and classic Hodgkin lymphoma (five cases). MTORC1 was also activated in the hyperplastic but not involuted follicles of HIV-assocd. lymphadenopathy in eight cases, supporting the notion that mTORC1 activation is a common feature of transformed lymphocytes irresp. of either their reactive or malignant phenotype. We also found that in B-cell lines that represent diffuse large B-cell lymphoma, Burkitt lymphoma, Epstein-Barr virus-infected lymphocytes, and human herpesvirus 8-pos. primary effusion lymphoma, inhibitors of Syk, MEK, and, seemingly, phosphoinositide 3 kinases suppressed mTORC1 activation, in particular when these inhibitors were used in combination. These findings indicate that AIDS-related lymphoma and other histol. similar types of lymphomas that are derived from transformed B lymphocytes may display clin. responses to inhibitors that directly target mTORC1 or, possibly, upstream activators of the mTORC1 pathway. [on SciFinder(R)]