title: Distinct patterns of DNA damage response and apoptosis correlate with Jak/Stat and PI3kinase response profiles in human acute myelogenous leukemia.
abstract: BACKGROUND
  Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in intracellular signaling responses. Here SCNP was used to characterize Acute Myeloid Leukemia (AML) disease subtypes based on survival, DNA damage response and apoptosis pathways.
  
  
  RESULTS
  Thirty four diagnostic non-M3 AML samples from patients with known clinical outcome were treated with a panel of myeloid growth factors and cytokines, as well as with apoptosis-inducing agents. Analysis of induced Jak/Stat and PI3K pathway responses in blasts from individual patient samples identified subgroups with distinct signaling profiles that were not seen in the absence of a modulator. In vitro exposure of patient samples to etoposide, a DNA damaging agent, revealed three distinct "DNA damage response (DDR)/apoptosis" profiles: 1) AML blasts with a defective DDR and failure to undergo apoptosis; 2) AML blasts with proficient DDR and failure to undergo apoptosis; 3) AML blasts with proficiency in both DDR and apoptosis pathways. Notably, AML samples from clinical responders fell within the "DDR/apoptosis" proficient profile and, as well, had low PI3K and Jak/Stat signaling responses. In contrast, samples from clinical non responders had variable signaling profiles often with in vitro apoptotic failure and elevated PI3K pathway activity. Individual patient samples often harbored multiple, distinct, leukemia-associated cell populations identifiable by their surface marker expression, functional performance of signaling pathway in the face of cytokine or growth factor stimulation, as well as their response to apoptosis-inducing agents.
  
  
  CONCLUSIONS
  Characterizing and tracking changes in intracellular pathway profiles in cell subpopulations both at baseline and under therapeutic pressure will likely have important clinical applications, potentially informing the selection of beneficial targeted agents, used either alone or in combination with chemotherapy.
authors.affiliation: Nodality, Inc, South San Francisco, California, United States of America.
authors.forename: David B
authors.initials: DB
authors.lastname: Rosen
authors.forename: Santosh
authors.initials: S
authors.lastname: Putta
authors.forename: Todd
authors.initials: T
authors.lastname: Covey
authors.forename: Ying-Wen
authors.initials: YW
authors.lastname: Huang
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cesano
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Fantl
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D050791:STAT Transcription Factors; D005047:Etoposide; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D019311:Staurosporine
references.citation: J Clin Oncol. 2010 Feb 1;28(4):596-604
references.pmid: 20026798
references.citation: Blood. 2002 Jan 1;99(1):252-7
references.pmid: 11756179
references.citation: Oncogene. 2008 Sep 18;27(41):5497-510
references.pmid: 18794884
references.citation: Hematology. 2009 Aug;14(4):204-12
references.pmid: 19635183
references.citation: Br J Haematol. 2007 Jun;137(5):387-400
references.pmid: 17488484
references.citation: Int Rev Cell Mol Biol. 2008;268:1-37
references.pmid: 18703402
references.citation: N Engl J Med. 2008 May 1;358(18):1909-18
references.pmid: 18450602
references.citation: Oncogene. 2007 Oct 15;26(47):6724-37
references.pmid: 17934481
references.citation: Exp Hematol. 2009 Jun;37(6):649-58
references.pmid: 19463767
references.citation: Cell Signal. 2009 Dec;21(12):1717-26
references.pmid: 19540337
references.citation: N Engl J Med. 1999 Sep 30;341(14):1051-62
references.pmid: 10502596
references.citation: Cytometry A. 2003 Oct;55(2):61-70
references.pmid: 14505311
references.citation: Crit Rev Oncol Hematol. 2007 Jun;62(3):214-26
references.pmid: 17368038
references.citation: Int J Hematol. 2005 Aug;82(2):93-9
references.pmid: 16146838
references.citation: Cell. 2004 Jul 23;118(2):217-28
references.pmid: 15260991
references.citation: Blood. 2010 Jan 21;115(3):453-74
references.pmid: 19880497
references.citation: Curr Opin Genet Dev. 2009 Feb;19(1):12-7
references.pmid: 19185485
references.citation: Blood. 2005 Aug 1;106(3):1063-6
references.pmid: 15840695
references.citation: Expert Opin Investig Drugs. 2009 Sep;18(9):1333-49
references.pmid: 19678801
references.citation: FEBS Lett. 2008 Apr 9;582(8):1266-70
references.pmid: 18282479
references.citation: Biochem Pharmacol. 2006 Mar 14;71(6):713-21
references.pmid: 16426581
references.citation: Lancet. 2006 Nov 25;368(9550):1894-907
references.pmid: 17126723
references.citation: Front Biosci. 2007 May 01;12:2807-20
references.pmid: 17485261
references.citation: J Immunol. 2006 Aug 1;177(3):1581-9
references.pmid: 16849466
references.citation: Nature. 2009 Oct 22;461(7267):1071-8
references.pmid: 19847258
references.citation: Clin Adv Hematol Oncol. 2009 Jul;7(7):448-51
references.pmid: 19701151
references.citation: Trends Biochem Sci. 2009 Mar;34(3):115-27
references.pmid: 19299143
references.citation: Hematology Am Soc Hematol Educ Program. 2008;:1-11
references.pmid: 19074046
references.citation: PLoS One. 2009 Nov 24;4(11):e7989
references.pmid: 19956772
references.citation: FEBS Lett. 1994 May 23;345(1):43-6
references.pmid: 8194597
references.citation: Cell Signal. 2007 Mar;19(3):454-65
references.pmid: 17085014
references.citation: Cell. 2007 Aug 10;130(3):395-8
references.pmid: 17693247
references.citation: Mol Cell. 2007 Dec 14;28(5):739-45
references.pmid: 18082599
references.citation: Cancer. 2007 Nov 1;110(9):1900-10
references.pmid: 17786921
references.citation: Exp Hematol. 2008 Apr;36(4):433-42
references.pmid: 18249061
references.citation: J Interferon Cytokine Res. 2005 Dec;25(12):733-44
references.pmid: 16375601
references.citation: Mol Cell Biol. 2008 Nov;28(21):6668-80
references.pmid: 18779318
references.citation: N Engl J Med. 2009 Sep 10;361(11):1058-66
references.pmid: 19657110
references.citation: Oncogene. 2000 May 15;19(21):2468-73
references.pmid: 10851045
references.citation: Cancer Cell. 2008 Oct 7;14(4):335-43
references.pmid: 18835035
references.citation: Clin Cancer Res. 2010 Jul 15;16(14):3721-33
references.pmid: 20525753
references.citation: J Biol Chem. 2007 May 11;282(19):14056-64
references.pmid: 17360704
references.citation: Crit Rev Oncol Hematol. 2007 Sep;63(3):215-30
references.pmid: 17658267
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Curr Opin Hematol. 2009 Mar;16(2):64-9
references.pmid: 19468266
references.citation: PLoS One. 2009;4(4):e5145
references.pmid: 19357769
references.citation: PLoS One. 2009 Jun 10;4(6):e5859
references.pmid: 19516899
references.citation: Cancer Treat Rev. 2010 Apr;36(2):142-50
references.pmid: 20056334
references.citation: Curr Opin Chem Biol. 2006 Feb;10(1):20-7
references.pmid: 16406766
references.citation: Curr Opin Hematol. 2009 Mar;16(2):98-104
references.pmid: 19468271
references.citation: Nature. 2006 May 25;441(7092):475-82
references.pmid: 16598206
references.citation: Ann N Y Acad Sci. 1993 Mar 20;677:265-80
references.pmid: 8494214
references.citation: Oncogene. 2000 May 15;19(21):2511-22
references.pmid: 10851050
references.citation: J Clin Invest. 2002 May;109(9):1139-42
references.pmid: 11994401
references.citation: Nat Rev Cancer. 2007 Dec;7(12):925-36
references.pmid: 18004398
references.citation: Blood. 2008 Feb 15;111(4):1903-12
references.pmid: 18042804
references.citation: Br J Haematol. 2003 Aug;122(3):454-6
references.pmid: 12877673
references.citation: Blood. 2005 Aug 15;106(4):1154-63
references.pmid: 15870183
references.citation: Clin Cancer Res. 2009 Jul 1;15(13):4263-9
references.pmid: 19549778
references.citation: Blood. 2006 Nov 1;108(9):3135-42
references.pmid: 16835385
references.citation: Nat Immunol. 2009 Apr;10(4):327-31
references.pmid: 19295628
references.citation: Blood. 2003 Apr 15;101(8):2940-54
references.pmid: 12480704
references.citation: J Leukoc Biol. 2009 Dec;86(6):1295-303
references.pmid: 19801497
references.citation: Nucleic Acids Res. 2008 Jun;36(11):3802-18
references.pmid: 18492722
references.citation: Nat Rev Cancer. 2006 Feb;6(2):146-55
references.pmid: 16491074
references.citation: Arthritis Res Ther. 2006;8 Suppl 2:S2
references.pmid: 16899106
references.citation: Clin Cancer Res. 2010 Jan 15;16(2):376-83
references.pmid: 20068082