title: B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition.
abstract: We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption of lysosome homeostasis characterized by lysosomal swelling, TFEB nuclear translocation, impaired maturation of lysosomal enzymes and incomplete autophagosome clearance. Furthermore, through genome-wide CRISPR knockout screening, we identified specific lysosomal genes (TFEB, CLCN7, OSTM1 and SNX10) as critical determinants of apilimod-induced cytotoxicity. Together these data highlight disruption of lysosome homeostasis through PIKFYVE inhibition as a novel anticancer mechanism in B-NHL and potentially other cancers.
authors.affiliation: a LAM Therapeutics , Guilford , CT , USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Gayle
authors.affiliation: a LAM Therapeutics , Guilford , CT , USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Landrette
authors.affiliation: a LAM Therapeutics , Guilford , CT , USA.
authors.forename: Neil
authors.identifier: http://orcid.org/0000-0002-9495-8388
authors.initials: N
authors.lastname: Beeharry
authors.affiliation: a LAM Therapeutics , Guilford , CT , USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Conrad
authors.affiliation: a LAM Therapeutics , Guilford , CT , USA.
authors.forename: Marylens
authors.initials: M
authors.lastname: Hernandez
authors.affiliation: a LAM Therapeutics , Guilford , CT , USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Beckett
authors.affiliation: b Department of Cell Biology , Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine , New Haven , CT , USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Ferguson
authors.affiliation: c Howard Hughes Medical Institute , Department of Genetics, Yale University School of Medicine , New Haven , CT , USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.affiliation: a LAM Therapeutics , Guilford , CT , USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rothberg
authors.affiliation: a LAM Therapeutics , Guilford , CT , USA.
authors.forename: Henri
authors.initials: H
authors.lastname: Lichenstein
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors
keywords: CLCN7; PIKFYVE; TFEB; apilimod; autophagy; lymphoma