Activation of CD44, a Receptor for Extracellular Matrix Components, Protects Chronic Lymphocytic Leukemia Cells from Spontaneous and Drug Induced Apoptosis Through MCL-1

Overview

Journal Leuk Lymphoma

Specialties Hematology
Oncology

Date 2011 Jun 9

PMID 21649540

Citations 59

Authors

Yair Herishanu

Federica Gibellini

Ndegwa Njuguna

Inbal Hazan-Halevy

Mohammed Farooqui

Sarah Bern

Keyvan Keyvanfar

Elinor Lee

Wyndham Wilson

Adrian Wiestner

Affiliations

Soon will be listed here.

Abstract

Survival of chronic lymphocytic leukemia (CLL) cells in vivo is supported by the tissue microenvironment, which includes components of the extracellular matrix. Interactions between tumor cells and the extracellular matrix are in part mediated by CD44, whose principal ligand is hyaluronic acid. Here, we show that CD44 is more highly expressed on CLL cells of the clinically more progressive immunglobulin heavy chain variable gene (IGHV)-unmutated subtype than on cells of the IGHV-mutated type. Engagement of CD44 activated the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK)/ERK pathways and increased myeloid cell leukemia sequence 1 (MCL-1) protein expression. Consistent with the induction of these anti-apoptotic mechanisms, CD44 protected CLL cells from spontaneous and fludarabine-induced apoptosis. Obatoclax, an antagonist of MCL-1, blocked the pro-survival effect of CD44. In addition, obatoclax synergized with fludarabine to induce apoptosis of CLL cells. In conclusion, components of the extracellular matrix may provide survival signals to CLL cells through engagement of CD44. Inhibition of MCL-1 is a promising strategy to reduce the anti-apoptotic effect of the microenvironment on CLL cells.

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