Activation of the PI3K/Akt Pathway in Plasma Cell Myeloma Is Associated with MAF and DEPTOR Overexpression and Favorable Response to Therapy.
Valentina Nardi, Heather Rochelle-Keyes, Tim Peterson, Massimo Loda, Liz Rosina, Noopur Raje, Aliyah R Sohani, David M Sabatini, Robert P Hasserjian. Massachusetts General Hospital, Boston; Whitehead Institute, Cambridge, MA; Dana Farber Cancer Institute, Boston, MA
Background: Plasma cell myeloma (PCM) is the second most common hematological malignancy and remains incurable. This neoplasm is characterized by a heterogeneous clinical course. Translocations involving the immunoglobulin heavy chain region with FGFR3 or MAF and TP53 deletions are adverse prognostic factors. One of the signaling pathways regulating survival and proliferation in PCM is the PI3K/Akt/mTOR pathway and its inhibition induces apoptosis in myeloma cells. Recently it has been shown that Maf overexpression in myeloma cells in vitro leads to markedly increased expression of a novel protein DEPTOR, which in turn causes hyperactivation of the PI3K/Akt pathway. We investigated activation of the PI3K/Akt pathway in plasma cell myeloma and correlated this with DEPTOR and Maf expression and clinical behavior of PCM.
Design: 43 consecutive PCM cases diagnosed and treated at a single institution over a 3-year period (2005-2007) with both an adequate bone marrow biopsy and clinical follow-up were analyzed by immunohistochemical stains using antibodies against Maf, DEPTOR and pAkt. The results were scored semi-quantitatively (0-3+) by two observers blinded to the clinical features of each case. Responses to therapy and overall survival were assessed.
Results: The median age was 66 y and median followup was 44 months. pAKT was expressed moderately or strongly in 23/36 (64%) evaluable cases. pAKT expression was positively correlated with DEPTOR (p<0.05) and Maf (p<0.05) expression; in particular, all DEPTOR+ cases showed cytoplasmic pAKT expression, while 6/12 DEPTOR- cases lacked cytoplasmic pAKT (p=0.006). pAKT+ PCM were less likely to progress on therapy (p=0.0004) and had a superior median overall survival of 57 months compared to 27 months for pAKT negative or weak cases (p=0.006). One case with MAF translocation and one with FGFR3 translocation were identified; both of these expressed pAKT and strongly expressed DEPTOR, but had a poor outcome typically associated with these translocations (survivals of 7 and 28 months, respectively).
Conclusions: These results suggest that PCM cases that display hyperactivation of the PI3K/Akt pathway and lack FGFR3 or MAF translocations have a relatively favorable response to current therapies; such cases may also benefit from inhibitors that target the PI3K/Akt pathway. The association of Maf and DEPTOR expression with pAKT+ PCM supports the recent in vitro studies linking these pathways.
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 245, Tuesday Morning