The role of phosphatidylinositol 3-kinase-δ in the immunomodulatory effects of lenalidomide in chronic lymphocytic leukemia.

Abstract:

:In patients with chronic lymphocytic leukemia (CLL), lenalidomide can promote humoral immune responses but also induces a distinct disease-specific toxicity of tumor flare and cytokine release. These CLL-specific events result from increased expression of costimulatory molecules on B cells. Here we demonstrate that lenalidomide activation of CLL cells depends on the phosphatidylinositol 3-kinase p110δ (PI3K-δ) pathway. Inhibition of PI3K-δ signaling by the PI3K-δ-inhibiting drug, CAL-101, or by siRNA knockdown of p110δ, abrogates CLL cell activation, costimulatory molecule expression, and vascular endothelial growth factor and basic fibroblast growth factor gene expression that is induced by lenalidomide. In addition, CAL-101 attenuates lenalidomide-mediated increases in immunoglobulin M production by normal B cells. Collectively, these data demonstrate the importance of PI3K-δ signaling for lenalidomide immune modulation. These findings may guide development of strategies for the treatment of CLL that combine lenalidomide with CAL-101, with other inhibitors of the PI3K-δ pathway, or with other agents that target downstream kinases of this signaling pathway.

journal_name

Blood

journal_title

Blood

authors

Herman SE,Lapalombella R,Gordon AL,Ramanunni A,Blum KA,Jones J,Zhang X,Lannutti BJ,Puri KD,Muthusamy N,Byrd JC,Johnson AJ

doi

10.1182/blood-2010-11-315705

subject

Has Abstract

pub_date

2011-04-21 00:00:00

pages

4323-7

issue

16

eissn

0006-4971

issn

1528-0020

pii

blood-2010-11-315705

journal_volume

117

pub_type

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