title: Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1.
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.
authors.affiliation: Hematology Branch, National Heart, Blood, and Lung Institute, National Cancer Institute, National Institutes of Health, Bethesda, MD20892-1202, USA.
authors.forename: Yair
authors.initials: Y
authors.lastname: Herishanu
authors.forename: Federica
authors.initials: F
authors.lastname: Gibellini
authors.forename: Ndegwa
authors.initials: N
authors.lastname: Njuguna
authors.forename: Inbal
authors.initials: I
authors.lastname: Hazan-Halevy
authors.forename: Mohammed
authors.initials: M
authors.lastname: Farooqui
authors.forename: Sarah
authors.initials: S
authors.lastname: Bern
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.forename: Elinor
authors.initials: E
authors.lastname: Lee
authors.forename: Wyndham
authors.initials: W
authors.lastname: Wilson
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D018960:Hyaluronan Receptors; D020928:Mitogen-Activated Protein Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; C579095:MCL1 protein, human