title: Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia.
abstract: The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-XL-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-XL We identify BCL-XL expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-XL results in synergistic killing in the majority of ALL xenografts. A notable exception is mixed lineage leukemia-rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups.
authors.affiliation: Walter Eliza Hall Institute of Medical Research, Melbourne, Australia; Royal Children's Hospital, Melbourne, Australia;
authors.forename: Seong Lin
authors.identifier: 0000-0002-9084-8974
authors.initials: SL
authors.lastname: Khaw
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia;
authors.forename: Santi
authors.initials: S
authors.lastname: Suryani
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia;
authors.forename: Kathryn
authors.initials: K
authors.lastname: Evans
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Richmond
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia;
authors.forename: Alissa
authors.initials: A
authors.lastname: Robbins
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, TX;
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.affiliation: Research Triangle Institute International, Research Triangle Park, NC;
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Erickson
authors.affiliation: Research Triangle Institute International, Research Triangle Park, NC;
authors.forename: Yuelong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, TX;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia;
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.affiliation: Walter Eliza Hall Institute of Medical Research, Melbourne, Australia; Faculty of Medicine, Dental and Health Sciences, University of Melbourne, Melbourne, Australia.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.affiliation: Walter Eliza Hall Institute of Medical Research, Melbourne, Australia; Faculty of Medicine, Dental and Health Sciences, University of Melbourne, Melbourne, Australia.
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia;
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D015321:Gene Rearrangement / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C497422:KMT2A protein, human; D012333:RNA, Messenger; D013449:Sulfonamides; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C579720:venetoclax