title: Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax.
abstract: The Bcl-2 family inhibitors venetoclax and navitoclax demonstrated potent antitumor activity in chronic lymphocytic leukemia patients, notably in reducing marrow load and adenopathy. Subsequent trials with venetoclax have been initiated in non-Hodgkin's lymphoma and multiple myeloma patients. Traditional preclinical models fall short either in faithfully recapitulating disease progression within such compartments or in allowing the direct longitudinal analysis of systemic disease. We show that intravenous inoculation of engineered RS4;11 (acute lymphoblastic leukemia) and Granta 519 (mantle cell lymphoma) bioluminescent reporter cell lines result in tumor engraftment of bone marrow, with additional invasion of the central nervous system in the case of Granta 519. Importantly, apoptosis induction and response of these systemically engrafted tumors to Bcl-2 family inhibitors alone or in combination with standard-of-care agents could be monitored longitudinally with optical imaging, and was more accurately reflective of the observed clinical response.
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Scott
authors.initials: S
authors.lastname: Ackler
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Chyla
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Jerry
authors.initials: J
authors.lastname: Clarin
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Kelly
authors.initials: K
authors.lastname: Foster
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Thomas
authors.initials: T
authors.lastname: McGonigal
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Sasmita
authors.initials: S
authors.lastname: Mishra
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Sally
authors.initials: S
authors.lastname: Schlessinger
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Morey L
authors.initials: ML
authors.lastname: Smith
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Leverson
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Erwin R
authors.initials: ER
authors.lastname: Boghaert
authors.affiliation: AbbVie Inc. North Chicago, Illinois.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hickson
keywords: Apoptosis; Bcl-2 family proteins; bioluminescent imaging; drug therapy; leukemia/lymphoma; systemic engraftment