Syk-dependent mTOR activation in follicular lymphoma cells

Abstract

The mammalian target of rapamycin (mTOR) is emerging as a promising target for antitumor therapy. However, the mechanism that contributes to its regulation in B lymphomas remains unknown. This study shows that in follicular lymphoma (FL) cells, mTOR is active because the cells displayed rapamycinsensitive phosphorylation of p70S6 kinase and 4E-BP1. Moreover, immunohistochemistry applied on lymph node tissue sections obtained from patients with FL revealed that, in most cases, p70S6 kinase was highly phosphorylated compared to normal tonsillar tissue. In FL cells, mTOR was under control of both phospholipase D (PLD) and phosphatidylinositol 3-kinase (PI3K). Moreover, we demonstrated that Syk plays a central role in mTOR activation because we found that both expression and activity are elevated compared to normal or chronic lymphocytic leukemia B cells. We also provide evidence that Syk operates through PLD-and PI3K-independent pathways. IntroductionNon-Hodgkin lymphoma (NHL) is the most commonly occurring malignant blood disease. Eighty-five percent of NHL belongs to the B lineage, and the most commonly occurring variety includes the diffuse large B-cell lymphoma (DLBCL). Follicular lymphoma (FL) is the second most common type of B-NHL and includes 35% to 40% of all adult lymphomas. FL is derived from germinal center follicle lymphoid cells. 1 FL is characterized by an indolent initial course, a favorable response to first-line therapy, and also recurrences followed by a refractory phase eventually complicated by histologic transformation. Although the prognosis of FL is variable, most patients with aggressive forms of FL (high FLIPI score) ultimately die from their disease and median survival is 5 to 8 years. 2 Despite the significant progress that has been made, mostly due to the introduction of rituximab combined with chemotherapy, further efforts are needed to identify new molecular targets in FL.In the vast majority of cases, FL cells display high expression of Bcl-2 as a consequence of t(14;18). 3,4 Based on the potent antiapoptotic properties of this protein, it has been proposed that not only is Bcl-2 a major, if not unique, causal factor for FL, but also that Bcl-2 overexpression represents a major obstacle for the eradication of tumor cells by chemotherapy, including that used in preparative regimens before stem cell transplantation. 5 However, approximately 10% to 15% of patients with FL are negative for Bcl-2. 6 Interestingly, clinical presentation, histopathologic findings, response to therapy, and clinical outcome in Bcl-2 ϩ patients are indistinguishable from those in Bcl-2 Ϫ FL patients. This observation suggests that, independently from Bcl-2, FL cells display alternative antiapoptotic pathways that ultimately interfere with the response to therapy. The recent identification of constitutively phosphorylated forms of AKT in FL histologic specimens supports this hypothesis. 7 The mammalian target of rapamycin, mTOR, is a 289-kDa evolutionarily conserved serine/threonine kinase that interacts and p...

mTOR as a multifunctional therapeutic target in HIV infection

“…In particular, they found that mTOR is activated in germinal centre cells and in the interfollicular areas, but not in the resting lymphocytes of the benign HIV-associated lymphadenopathy. Along with the reported occurrence of mTOR activation in non-HIV-associated lymphomas [56], these data suggest that the use of mTOR inhibitors could have potential therapeutic effects in HIV-associated and non-HIV-associated lymphomas. Although large studies to support the potential use of mTOR inhibitors against HIV-associated lymphomas are not available, it is interesting to observe that post-transplant lymphoproliferative disorder (PTLD)-type cell lines are highly sensitive to mTOR inhibition [57] and that substitution of immunosuppressive therapies based on inhibitors of calcineurin with mTORinhibitor-based therapies in organ-transplanted patients reduced the occurrence of PTLD lesions [58].…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…161,163,164 As mentioned before the Rheb GTPase is an activator of mTORC1. Rheb is highly expressed in some human lymphomas 31,[165][166][167] and other cancers. 168 Rheb activity is dependent on farnesylation.…”

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

“…These include drugs that target Notch, MAP kinase interacting kinase (MNK), the tyrosine kinase Syk, and aurora kinase. [117][118][119][120] 4. Targeting PI3K/AKT/mTOR in Pediatric Hematologic Malignancies…”