title: The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells.
abstract: CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNFα-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ; Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fiorcari
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Wells S
authors.initials: WS
authors.lastname: Brown
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: McIntyre
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.affiliation: Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Maffei
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Mariela
authors.initials: M
authors.lastname: Sivina
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoellenriegel
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.affiliation: Gilead Sciences, Inc. Seattle, Washington, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lannutti
authors.affiliation: Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D039041:Integrin alpha4beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D039041:Integrin alpha4beta1; D016023:Integrins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D019010:Vascular Cell Adhesion Molecule-1; C552946:idelalisib