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
Bloodjournal_title
Bloodauthors
Herman SE,Lapalombella R,Gordon AL,Ramanunni A,Blum KA,Jones J,Zhang X,Lannutti BJ,Puri KD,Muthusamy N,Byrd JC,Johnson AJdoi
10.1182/blood-2010-11-315705subject
Has Abstractpub_date
2011-04-21 00:00:00pages
4323-7issue
16eissn
0006-4971issn
1528-0020pii
blood-2010-11-315705journal_volume
117pub_type
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