title: Inhibition of GATE-16 attenuates ATRA-induced neutrophil differentiation of APL cells and interferes with autophagosome formation.
abstract: Autophagy is an intracellular bulk degradation process involved in cell survival upon stress induction, but also with a newly identified function in myeloid differentiation. The autophagy-related (ATG)8 protein family, including the GABARAP and LC3 subfamilies, is crucial for autophagosome biogenesis. In order to evaluate the significance of the GABARAPs in the pathogenesis of acute myeloid leukemia (AML), we compared their expression in primary AML patient samples, CD34(+) progenitor cells and in granulocytes from healthy donors. GABARAPL1 and GABARAPL2/GATE-16, but not GABARAP, were significantly downregulated in particular AML subtypes compared to normal granulocytes. Moreover, the expression of GABARAPL1 and GATE-16 was significantly induced during ATRA-induced neutrophil differentiation of acute promyelocytic leukemia cells (APL). Lastly, knocking down GABARAPL2/GATE-16 in APL cells attenuated neutrophil differentiation and decreased autophagic flux. In conclusion, low GABARAPL2/GATE-16 expression is associated with an immature myeloid leukemic phenotype and these proteins are necessary for neutrophil differentiation of APL cells.
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brigger
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Torbett
authors.forename: Joy
authors.initials: J
authors.lastname: Chen
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fey
authors.forename: Mario P
authors.initials: MP
authors.lastname: Tschan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071190:Autophagy-Related Protein 8 Family; D002454:Cell Differentiation; D002460:Cell Line; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology*; D014212:Tretinoin / Q000378:metabolism*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D051017:Apoptosis Regulatory Proteins; D000071190:Autophagy-Related Protein 8 Family; C116741:GABARAP protein, human; C430503:GABARAPL1 protein, human; C498698:GABARAPL2 protein, human; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D014212:Tretinoin
keywords: AML; APL; GABARAP; GABARAPL1; GATE-16; Neutrophil differentiation
references.citation: N Engl J Med. 2003 Aug 21;349(8):743-52
references.pmid: 12930926
references.citation: Blood. 2008 Aug 15;112(4):1493-502
references.pmid: 18539900
references.citation: Nature. 2008 Feb 28;451(7182):1069-75
references.pmid: 18305538
references.citation: Br J Haematol. 2005 Jan;128(1):59-65
references.pmid: 15606550
references.citation: Annu Rev Pathol. 2011;6:345-64
references.pmid: 21073338
references.citation: EMBO J. 2010 Jun 2;29(11):1792-802
references.pmid: 20418806
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):832-7
references.pmid: 20080761
references.citation: Autophagy. 2011 Jul;7(7):683-8
references.pmid: 21460636
references.citation: Blood. 2012 May 10;119(19):4527-31
references.pmid: 22452982
references.citation: J Clin Oncol. 1997 Dec;15(12):3496-506
references.pmid: 9396403
references.citation: Int J Biochem Cell Biol. 2003 May;35(5):553-61
references.pmid: 12672448
references.citation: Dev Cell. 2008 Sep;15(3):344-357
references.pmid: 18804433
references.citation: Genome Biol. 2011 Jul 27;12(7):226
references.pmid: 21867568
references.citation: Br J Haematol. 2010 Apr;149(1):55-64
references.pmid: 20096012
references.citation: Nutr Cancer. 2011;63(4):479-94
references.pmid: 21541902
references.citation: Blood. 2010 Sep 30;116(13):2324-31
references.pmid: 20574048
references.citation: Cell Res. 2012 Feb;22(2):432-5
references.pmid: 22184008
references.citation: Mol Biol Cell. 2008 Aug;19(8):3290-8
references.pmid: 18508918
references.citation: J Exp Med. 2011 Mar 14;208(3):455-67
references.pmid: 21339326
references.citation: Leuk Res. 2012 Dec;36(12):1552-6
references.pmid: 22981223
references.citation: J Biol Chem. 2003 Oct 31;278(44):42750-60
references.pmid: 12917399
references.citation: J Intern Med. 2010 Nov;268(5):410-8
references.pmid: 20964733
references.citation: Semin Cancer Biol. 2011 Dec;21(6):397-404
references.pmid: 21945348
references.citation: Autophagy. 2011 Oct;7(10):1098-107
references.pmid: 21597319
references.citation: Biochimie. 2012 Mar;94(3):748-58
references.pmid: 22120110
references.citation: Blood. 2010 Sep 30;116(13):2200-1
references.pmid: 20884808
references.citation: Oncogene. 2008 Sep 25;27(43):5706-16
references.pmid: 18521079
references.citation: Mol Cell Biol. 2012 Jan;32(1):226-39
references.pmid: 22025678
references.citation: Blood. 2012 May 24;119(21):4963-70
references.pmid: 22498738
references.citation: Autophagy. 2012 Apr;8(4):445-544
references.pmid: 22966490
references.citation: Mol Cancer Ther. 2010 Aug;9(8):2232-42
references.pmid: 20663926
references.citation: J Biol Chem. 1996 Nov 8;271(45):28593-600
references.pmid: 8910489
references.citation: Antioxid Redox Signal. 2011 Jun;14(11):2201-14
references.pmid: 20712405
references.citation: Cell Mol Life Sci. 2004 Jun;61(12):1475-84
references.pmid: 15197471
references.citation: Biochim Biophys Acta. 2009 Sep;1793(9):1461-4
references.pmid: 19168096
references.citation: Exp Cell Res. 2012 Jul 1;318(11):1187-92
references.pmid: 22245582
references.citation: Blood. 2004 Apr 15;103(8):2908-13
references.pmid: 15070662
references.citation: Oncol Lett. 2013 Feb;5(2):411-416
references.pmid: 23420500
references.citation: Autophagy. 2011 Oct;7(10):1132-44
references.pmid: 21673516
references.citation: Leuk Res. 2010 Mar;34(3):393-8
references.pmid: 19775754
references.citation: Biochim Biophys Acta. 2003 Aug 18;1641(2-3):145-56
references.pmid: 12914955
references.citation: Clin Cancer Res. 2013 Apr 1;19(7):1651-9
references.pmid: 23322901