title: HOXA/PBX3 knockdown impairs growth and sensitizes cytogenetically normal acute myeloid leukemia cells to chemotherapy.
abstract: The cytogenetically normal subtype of acute myeloid leukemia is associated with an intermediate risk which complicates therapeutic options. Lower overall HOX/TALE expression appears to correlate with more favorable prognosis/better response to treatment in some leukemias and solid cancer. The functional significance of the associated gene expression and response to chemotherapy is not known. Three independent microarray datasets obtained from large cohorts of patients along with quantitative polymerase chain reaction validation were used to identify a four-gene HOXA/TALE signature capable of prognostic stratification. Biochemical analysis was used to identify interactions between the four encoded proteins and targeted knockdown used to examine the functional importance of sustained expression of the signature in leukemia maintenance and response to chemotherapy. An 11 HOXA/TALE code identified in an intermediate-risk group of patients (n=315) compared to a group with a favorable risk (n=105) was reduced to a four-gene signature of HOXA6, HOXA9, PBX3 and MEIS1 by iterative analysis of independent platforms. This signature maintained the favorable/intermediate risk partition and where applicable, correlated with overall survival in cytogenetically normal acute myeloid leukemia. We further showed that cell growth and function are dependent on maintained levels of these core genes and that direct targeting of HOXA/PBX3 sensitizes cytogenetically normal acute myeloid leukemia cells to standard chemotherapy. Together the data support a key role for HOXA/TALE in cytogenetically normal acute myeloid leukemia and demonstrate that targeting of clinically significant HOXA/PBX3 elements may provide therapeutic benefit to patients with this subtype of leukemia.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Northern Ireland, UK.
authors.forename: Glenda J
authors.initials: GJ
authors.lastname: Dickson
authors.forename: Fabio G
authors.initials: FG
authors.lastname: Liberante
authors.forename: Laura M
authors.initials: LM
authors.lastname: Kettyle
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: O'Hagan
authors.forename: Damian P J
authors.initials: DP
authors.lastname: Finnegan
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.forename: Mary Frances
authors.initials: MF
authors.lastname: McMullin
authors.forename: Terry R J
authors.initials: TR
authors.lastname: Lappin
authors.forename: Ken I
authors.initials: KI
authors.lastname: Mills
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D020732:Cytogenetic Analysis / Q000379:methods*; D055785:Gene Knockdown Techniques / Q000379:methods; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; C539638:Hoxa6 protein, human; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C097899:homeobox protein HOXA9; C090466:proto-oncogene protein Pbx3
references.citation: Mol Cell Biol. 2004 Jun;24(12):5324-31
references.pmid: 15169896
references.citation: Mol Cell Biol. 2001 Jan;21(1):224-34
references.pmid: 11113197
references.citation: Exp Hematol. 2010 Nov;38(11):1074-1086.e1-5
references.pmid: 20655978
references.citation: N Engl J Med. 2010 Dec 16;363(25):2424-33
references.pmid: 21067377
references.citation: Am J Pathol. 2004 Oct;165(4):1343-50
references.pmid: 15466398
references.citation: Blood. 2002 Jan 1;99(1):121-9
references.pmid: 11756161
references.citation: Blood. 2010 Apr 8;115(14):2910-8
references.pmid: 20130239
references.citation: Exp Hematol. 2009 Mar;37(3):322-33.e3
references.pmid: 19157684
references.citation: Blood. 2010 Jul 22;116(3):354-65
references.pmid: 20385793
references.citation: Blood. 2012 Oct 11;120(15):2963-72
references.pmid: 22915647
references.citation: Genes Chromosomes Cancer. 2003 Jun;37(2):149-58
references.pmid: 12696063
references.citation: N Engl J Med. 2004 Apr 15;350(16):1605-16
references.pmid: 15084693
references.citation: Blood. 2013 Feb 21;121(8):1422-31
references.pmid: 23264595
references.citation: BMC Bioinformatics. 2007 Nov 15;8:446
references.pmid: 18005434
references.citation: Blood. 1997 Mar 15;89(6):1922-30
references.pmid: 9058712
references.citation: Blood. 2003 Jun 1;101(11):4589-97
references.pmid: 12576328
references.citation: Leukemia. 2002 Feb;16(2):186-95
references.pmid: 11840284
references.citation: Oncol Rep. 2004 Nov;12(5):1115-20
references.pmid: 15492802
references.citation: EMBO J. 1998 Jul 1;17(13):3714-25
references.pmid: 9649441
references.citation: Hematol Oncol Clin North Am. 2011 Dec;25(6):1135-61, vii
references.pmid: 22093581
references.citation: J Clin Oncol. 2010 Feb 1;28(4):586-95
references.pmid: 20038732
references.citation: Blood. 2005 Dec 1;106(12):3733-9
references.pmid: 16076867
references.citation: Mol Cell Biol. 1991 Dec;11(12):6149-57
references.pmid: 1682799
references.citation: Blood. 2011 Jul 28;118(4):1069-76
references.pmid: 21596848
references.citation: Blood. 2010 Jan 21;115(3):453-74
references.pmid: 19880497
references.citation: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references.pmid: 12582260
references.citation: Mol Cell Biol. 1999 Apr;19(4):3051-61
references.pmid: 10082572
references.citation: Haematologica. 2011 Oct;96(10):1548-51
references.pmid: 21791474
references.citation: Blood. 2003 Feb 15;101(4):1558-65
references.pmid: 12560242
references.citation: J Clin Oncol. 2010 May 20;28(15):2529-37
references.pmid: 20406941
references.citation: Blood. 2005 Dec 1;106(12):3740-6
references.pmid: 16051734
references.citation: Blood. 2012 Mar 8;119(10):2314-24
references.pmid: 22251480
references.citation: Leuk Res. 2009 Sep;33(9):1189-93
references.pmid: 19428106
references.citation: Methods Mol Biol. 2009;538:369-93
references.pmid: 19277582
references.citation: Br J Haematol. 2002 Aug;118(2):385-400
references.pmid: 12139722
references.citation: J Clin Oncol. 2011 Feb 10;29(5):475-86
references.pmid: 21220609
references.citation: Blood. 2005 Dec 1;106(12):3747-54
references.pmid: 16109776
references.citation: J Nucl Med. 2006 May;47(5):827-36
references.pmid: 16644753
references.citation: Oncogene. 1996 Nov 21;13(10):2235-42
references.pmid: 8950991
references.citation: Genes Dev. 2007 Nov 1;21(21):2762-74
references.pmid: 17942707
references.citation: Leukemia. 2012 Mar;26(3):554-7
references.pmid: 21904384
references.citation: BMC Bioinformatics. 2009 Dec 15;10:422
references.pmid: 20003504