title: Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia.
abstract: Survival in infants younger than 1 year who have acute lymphoblastic leukemia (ALL) is inferior whether MLL is rearranged (R) or germline (G). MLL translocations confer chemotherapy resistance, and infants experience excess complications. We characterized in vitro sensitivity to the pan-antiapoptotic BCL-2 family inhibitor obatoclax mesylate in diagnostic leukemia cells from 54 infants with ALL/bilineal acute leukemia because of the role of prosurvival BCL-2 proteins in resistance, their imbalanced expression in infant ALL, and evidence of obatoclax activity with a favorable toxicity profile in early adult leukemia trials. Overall, half maximal effective concentrations (EC50s) were lower than 176 nM (the maximal plasma concentration [Cmax] with recommended adult dose) in 76% of samples, whether in MLL-AF4, MLL-ENL, or other MLL-R or MLL-G subsets, and regardless of patients' poor prognostic features. However, MLL status and partner genes correlated with EC50. Combined approaches including flow cytometry, Western blot, obatoclax treatment with death pathway inhibition, microarray analyses, and/or electron microscopy indicated a unique killing mechanism involving apoptosis, necroptosis, and autophagy in MLL-AF4 ALL cell lines and primary MLL-R and MLL-G infant ALL cells. This in vitro obatoclax activity and its multiple killing mechanisms across molecular cytogenetic subsets provide a rationale to incorporate a similarly acting compound into combination strategies to combat infant ALL.
authors: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Karen A
authors: KA
authors: Urtishak
authors: Alena Y Z
authors: AY
authors: Edwards
authors: Li-San
authors: LS
authors: Wang
authors: Amanda
authors: A
authors: Hudome
authors: Blaine W
authors: BW
authors: Robinson
authors: Jeffrey S
authors: JS
authors: Barrett
authors: Kajia
authors: K
authors: Cao
authors: Lori
authors: L
authors: Cory
authors: Jonni S
authors: JS
authors: Moore
authors: Andrew D
authors: AD
authors: Bantly
authors: Qian-Chun
authors: QC
authors: Yu
authors: I-Ming L
authors: IM
authors: Chen
authors: Susan R
authors: SR
authors: Atlas
authors: Cheryl L
authors: CL
authors: Willman
authors: Mondira
authors: M
authors: Kundu
authors: Andrew J
authors: AJ
authors: Carroll
authors: Nyla A
authors: NA
authors: Heerema
authors: Meenakshi
authors: M
authors: Devidas
authors: Joanne M
authors: JM
authors: Hilden
authors: ZoAnn E
authors: ZE
authors: Dreyer
authors: Stephen P
authors: SP
authors: Hunger
authors: Gregory H
authors: GH
authors: Reaman
authors: Carolyn A
authors: CA
authors: Felix
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007211:Indoles; D007223:Infant; D007231:Infant, Newborn; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009336:Necrosis / Q000188:drug therapy; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C497422:KMT2A protein, human; C113855:MLL-AF4 fusion protein, human; C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C520962:obatoclax
references: Clin Cancer Res. 2008 Dec 15;14(24):8295-301
references: 19088047
references: Blood. 2005 Nov 15;106(10):3559-66
references: 16046533
references: Blood. 2010 Feb 18;115(7):1394-405
references: 19880498
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7
references: 18040043
references: Blood. 2007 May 15;109(10):4441-9
references: 17227835
references: Blood. 2010 Feb 4;115(5):1018-25
references: 19965632
references: Blood. 2006 Jul 15;108(2):441-51
references: 16556894
references: Blood. 2008 Apr 1;111(7):3322-30
references: 18362212
references: Autophagy. 2008 Feb;4(2):151-75
references: 18188003
references: Sci Signal. 2010 Mar 30;3(115):re4
references: 20354226
references: Cancer Res. 2008 May 1;68(9):3413-20
references: 18451169
references: Cancer Lett. 2008 Feb 8;259(2):127-37
references: 18082322
references: Br J Haematol. 2001 Mar;112(3):706-13
references: 11260076
references: Oncogene. 2008 Dec;27 Suppl 1:S137-48
references: 19641499
references: Lancet. 2007 Jul 21;370(9583):240-250
references: 17658395
references: Nat Chem Biol. 2005 Jul;1(2):112-9
references: 16408008
references: Cell Death Differ. 2009 Jan;16(1):3-11
references: 18846107
references: Pediatr Blood Cancer. 2012 Nov;59(5):834-9
references: 22488662
references: Clin Cancer Res. 2009 Jan 1;15(1):150-9
references: 19118042
references: Nat Cell Biol. 2004 Dec;6(12):1221-8
references: 15558033
references: J Clin Invest. 2010 Apr;120(4):1310-23
references: 20200450
references: Methods Cell Biol. 2011;103:55-98
references: 21722800
references: Leukemia. 1998 Oct;12(10):1561-4
references: 9766500
references: Clin Cancer Res. 2010 Aug 1;16(15):3923-32
references: 20538760
references: Cell Death Dis. 2010 Sep 16;1:e76
references: 21364679
references: Blood. 2009 Jun 11;113(24):6061-8
references: 19289854
references: Br J Haematol. 2008 Jun;141(6):827-39
references: 18422996
references: J Pathol. 2010 May;221(1):3-12
references: 20225336
references: Cell. 2005 Sep 23;122(6):927-39
references: 16179260
references: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20037-42
references: 18077432
references: J Immunol Methods. 1995 Dec 27;188(2):219-28
references: 8551050
references: Cell Death Differ. 2009 Jul;16(7):1030-9
references: 19390557
references: Blood. 2009 Jan 8;113(2):299-305
references: 18931344
references: Exp Hematol. 2006 Dec;34(12):1663-9
references: 17157163
references: Nat Rev Mol Cell Biol. 2010 Oct;11(10):700-14
references: 20823910
references: Nat Chem Biol. 2008 May;4(5):313-21
references: 18408713
references: FASEB J. 1996 Apr;10(5):587-97
references: 8621058
references: Anticancer Drugs. 1997 Nov;8(10):903-10
references: 9436633