BACKGROUND: Programmed cell death has been traditionally related with caspase activation. However, it is now accepted that caspase-independent forms of programmed cell death also regulate cell death. In chronic lymphocytic leukemia, CD47 ligation induces one of these alternative forms of cell death: type III programmed cell death. This poorly understood process is characterized by cytoplasmic hallmarks, such as mitochondrial damage. To gain insights into the molecular pathways regulating type III programmed cell death in chronic lymphocytic leukemia, we performed extensive biochemical and cell biology assessments. DESIGN AND METHODS: After CD47 triggering, purified B-cells from 20 patients with chronic lymphocytic leukemia were studied by flow cytometry, immunofluorescence and three-dimensional imaging, immunoblotting, electron microscopy, and fibrillar/globular actin measurements. Finally, we subjected CD47-treated chronic lymphocytic leukemia cells to a phagocytosis assay. RESULTS: We first confirmed that induction of type III programmed cell death is an efficient means of triggering cell death in chronic lymphocytic leukemia. Further, we demonstrated that the signaling events induced by CD47 ligation provoked a reduction in cell size. This alteration is related to F-actin disruption, as the two other cytoskeleton networks, microtubules and intermediate filaments, remain undisturbed in type III programmed cell death. Strikingly, we revealed that the pharmacological modulation of F-actin dynamics regulated this type of death. Finally, our data delineated a new programmed cell death pathway in chronic lymphocytic leukemia initiated by CD47 triggering, and followed by serine protease activation, F-actin rearrangement, mitochondrial damage, phosphatidylserine exposure, and cell clearance. CONCLUSIONS: Our work reveals a key molecular tool in the modulation of cell death in chronic lymphocytic leukemia: F-actin. By assessing the regulation of F-actin and type III programmed cell death, this analysis provides new options for destroying chronic lymphocytic leukemia cells, such as a combination of therapies based on apoptosis regulators (e.g., caspases, Bcl-2, Bax) along with alternative therapies based on type III death effectors (e.g., F-actin).
BACKGROUND: Programmed cell death has been traditionally related with caspase activation. However, it is now accepted that caspase-independent forms of programmed cell death also regulate cell death. In chronic lymphocytic leukemia, CD47 ligation induces one of these alternative forms of cell death: type III programmed cell death. This poorly understood process is characterized by cytoplasmic hallmarks, such as mitochondrial damage. To gain insights into the molecular pathways regulating type III programmed cell death in chronic lymphocytic leukemia, we performed extensive biochemical and cell biology assessments. DESIGN AND METHODS: After CD47 triggering, purified B-cells from 20 patients with chronic lymphocytic leukemia were studied by flow cytometry, immunofluorescence and three-dimensional imaging, immunoblotting, electron microscopy, and fibrillar/globular actin measurements. Finally, we subjected CD47-treated chronic lymphocytic leukemia cells to a phagocytosis assay. RESULTS: We first confirmed that induction of type III programmed cell death is an efficient means of triggering cell death in chronic lymphocytic leukemia. Further, we demonstrated that the signaling events induced by CD47 ligation provoked a reduction in cell size. This alteration is related to F-actin disruption, as the two other cytoskeleton networks, microtubules and intermediate filaments, remain undisturbed in type III programmed cell death. Strikingly, we revealed that the pharmacological modulation of F-actin dynamics regulated this type of death. Finally, our data delineated a new programmed cell death pathway in chronic lymphocytic leukemia initiated by CD47 triggering, and followed by serine protease activation, F-actin rearrangement, mitochondrial damage, phosphatidylserine exposure, and cell clearance. CONCLUSIONS: Our work reveals a key molecular tool in the modulation of cell death in chronic lymphocytic leukemia: F-actin. By assessing the regulation of F-actin and type III programmed cell death, this analysis provides new options for destroying chronic lymphocytic leukemia cells, such as a combination of therapies based on apoptosis regulators (e.g., caspases, Bcl-2, Bax) along with alternative therapies based on type III death effectors (e.g., F-actin).
Authors: Atlantis Russ; Anh B Hua; William R Montfort; Bushra Rahman; Irbaz Bin Riaz; Muhammad Umar Khalid; Jennifer S Carew; Steffan T Nawrocki; Daniel Persky; Faiz Anwer Journal: Blood Rev Date: 2018-04-14 Impact factor: 8.250
Authors: Ekkehard Mössner; Peter Brünker; Samuel Moser; Ursula Püntener; Carla Schmidt; Sylvia Herter; Roger Grau; Christian Gerdes; Adam Nopora; Erwin van Puijenbroek; Claudia Ferrara; Peter Sondermann; Christiane Jäger; Pamela Strein; Georg Fertig; Thomas Friess; Christine Schüll; Sabine Bauer; Joseph Dal Porto; Christopher Del Nagro; Karim Dabbagh; Martin J S Dyer; Sibrand Poppema; Christian Klein; Pablo Umaña Journal: Blood Date: 2010-03-01 Impact factor: 22.113
Authors: Waleed Alduaij; Andrei Ivanov; Jamie Honeychurch; Eleanor J Cheadle; Sandeep Potluri; Sean H Lim; Kazuyuki Shimada; Claude H T Chan; Alison Tutt; Stephen A Beers; Martin J Glennie; Mark S Cragg; Tim M Illidge Journal: Blood Date: 2011-03-04 Impact factor: 22.113
Authors: H Jiang; C Acharya; G An; M Zhong; X Feng; L Wang; N Dasilva; Z Song; G Yang; F Adrian; L Qiu; P Richardson; N C Munshi; Y-T Tai; K C Anderson Journal: Leukemia Date: 2015-09-04 Impact factor: 11.528
Authors: Caroline S Breton; Aimable Nahimana; Dominique Aubry; Julie Macoin; Pierre Moretti; Martin Bertschinger; Samuel Hou; Michel A Duchosal; Jonathan Back Journal: J Hematol Oncol Date: 2014-04-14 Impact factor: 17.388