Bruton's tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.

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BlankBruton's tyrosine kinase represents a promising therapeutic target for

treatment of chronic lymphocytic leukemia and is effectively targeted by

PCI-32765.

SE Herman, AL Gordon, E Hertlein, A Ramanunni, X Zhang, S Jaglowski, J Flynn, J

, KA Blum, JJ Buggy, A Hamdy, AJ , and JC Byrd

Blood, March 21, 2011;

Integrated Biomedical Science Graduate Program, The Ohio State University

Medical Center, Columbus, OH, United States;

B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic

leukemia (CLL). Bruton's Tyrosine Kinase (BTK) is essential to BCR signaling and

in knock out mouse models its mutation has a relatively B-cell specific

phenotype. Herein, we demonstrate BTK protein and mRNA are significantly over

expressed in CLL as compared to normal B-cells. While BTK is not always

constitutively active in CLL cells, BCR or CD40 signaling is accompanied by

effective activation of this pathway. Using the irreversible BTK inhibitor

PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than

that observed in normal B-cells. No influence of PCI-32765 on T-cell survival is

observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in

inhibition of BTK tyrosine phosphorylation and also effectively abrogates

down-stream survival pathways activated by this kinase including ERK1/2, PI3K,

and NF-?B. Additionally, PCI-32765 inhibits activation-induced proliferation of

CLL cells in vitro, effectively blocks survival signals provided externally to

CLL cells from the microenvironment including soluble factors (CD40L, BAFF,

IL-6, IL-4, and TNF-?), fibronectin engagement and stromal cell contact. Based

upon these collective data, future efforts targeting BTK with the irreversible

inhibitor PCI-32765 in clinical trials of CLL patients is warranted.

PMID: 21422473 .