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 Blood, 15 December 2006, Vol. 108, No. 13, pp. 4178-4186.
Prepublished online as a Blood First Edition Paper on August 31, 2006; DOI 10.1182/blood-2006-04-016907.

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Submitted April 12, 2006
Accepted July 24, 2006

Role of phosphatidylinositol 3'- Kinase/AKT pathway in diffuse large B-cell lymphoma survival

Shahab Uddin*, Azhar R Hussain, Abdul K Siraj, Pulicat S Manogaran, Naif A Al-Jomah, Azadali Moorji, Valerie Atizado, Fouad Al-Dayel, Asim Belgaumi, Hassan El-Solh, Adnan Ezzat, Prashant Bavi, and Khawla S Al-Kuraya

King Faisal Specialist Hospital Research Center, Riyadh, Saudi Arabia

* Corresponding author; email: shahab{at}kfshrc.edu.sa.

Phosphatidylinositol 3-kinase (PI3’ -kinase) is a key player in cell growth signaling in a number of lymphoid malignancies, but its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. Therefore, we investigated the role of the PI3’ -kinase/AKT pathway in a panel of 5 DLBCL cell lines and 100 clinical samples. Inhibition of PI3’ -kinase by a specific inhibitor, LY294002, induced apoptosis in SUDHL4, SUDHL5 and SUDHL10 (LY-sensitive), while SUDHL8 and OCI-LY19 (LY-resistant) were refractory to LY294002-induced apoptosis. AKT was phosphorylated in 5/5 DLBCL cell lines and inhibition of PI3’ -kinase caused de-phosphorylation/inactivation of constitutively active AKT, FOXO transcription factor and GSK3 in LY-sensitive cell lines. In addition, there was a decrease in the expression level of inhibitory apoptotic protein, XIAP in the DLBCL cell lines sensitive to LY294002 after treatment. However, no effect was observed in XIAP protein levels in the resistant DLBCL cell lines following LY294002 treatment. Finally, using immunohistochemistry, p-AKT was detected in 52% of DLBCL tumors tested. Furthermore, in univariate analysis, expression was associated with short survival. In multivariate analysis, this correlation was no longer significant. Altogether, these results suggest that PI3'-kinase/AKT pathway may be a potential target for therapeutic intervention in diffuse large B-cell lymphoma.


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