Distinct patterns of DNA damage response and apoptosis correlate with Jak/Stat and PI3kinase response profiles in human acute myelogenous leukemia.
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.
Rosen
David B
DB
Nodality, Inc, South San Francisco, California, United States of America.
Putta
Santosh
S
Covey
Todd
T
Huang
Ying-Wen
YW
Nolan
Garry P
GP
Cesano
Alessandra
A
Minden
Mark D
MD
Fantl
Wendy J
WJ
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
D050791:STAT Transcription Factors; D005047:Etoposide; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D019311:Staurosporine
J Clin Oncol. 2010 Feb 1;28(4):596-604
20026798
Blood. 2002 Jan 1;99(1):252-7
11756179
Oncogene. 2008 Sep 18;27(41):5497-510
18794884
Hematology. 2009 Aug;14(4):204-12
19635183
Br J Haematol. 2007 Jun;137(5):387-400
17488484
Int Rev Cell Mol Biol. 2008;268:1-37
18703402
N Engl J Med. 2008 May 1;358(18):1909-18
18450602
Oncogene. 2007 Oct 15;26(47):6724-37
17934481
Exp Hematol. 2009 Jun;37(6):649-58
19463767
Cell Signal. 2009 Dec;21(12):1717-26
19540337
N Engl J Med. 1999 Sep 30;341(14):1051-62
10502596
Cytometry A. 2003 Oct;55(2):61-70
14505311
Crit Rev Oncol Hematol. 2007 Jun;62(3):214-26
17368038
Int J Hematol. 2005 Aug;82(2):93-9
16146838
Cell. 2004 Jul 23;118(2):217-28
15260991
Blood. 2010 Jan 21;115(3):453-74
19880497
Curr Opin Genet Dev. 2009 Feb;19(1):12-7
19185485
Blood. 2005 Aug 1;106(3):1063-6
15840695
Expert Opin Investig Drugs. 2009 Sep;18(9):1333-49
19678801
FEBS Lett. 2008 Apr 9;582(8):1266-70
18282479
Biochem Pharmacol. 2006 Mar 14;71(6):713-21
16426581
Lancet. 2006 Nov 25;368(9550):1894-907
17126723
Front Biosci. 2007 May 01;12:2807-20
17485261
J Immunol. 2006 Aug 1;177(3):1581-9
16849466
Nature. 2009 Oct 22;461(7267):1071-8
19847258
Clin Adv Hematol Oncol. 2009 Jul;7(7):448-51
19701151
Trends Biochem Sci. 2009 Mar;34(3):115-27
19299143
Hematology Am Soc Hematol Educ Program. 2008;:1-11
19074046
PLoS One. 2009 Nov 24;4(11):e7989
19956772
FEBS Lett. 1994 May 23;345(1):43-6
8194597
Cell Signal. 2007 Mar;19(3):454-65
17085014
Cell. 2007 Aug 10;130(3):395-8
17693247
Mol Cell. 2007 Dec 14;28(5):739-45
18082599
Cancer. 2007 Nov 1;110(9):1900-10
17786921
Exp Hematol. 2008 Apr;36(4):433-42
18249061
J Interferon Cytokine Res. 2005 Dec;25(12):733-44
16375601
Mol Cell Biol. 2008 Nov;28(21):6668-80
18779318
N Engl J Med. 2009 Sep 10;361(11):1058-66
19657110
Oncogene. 2000 May 15;19(21):2468-73
10851045
Cancer Cell. 2008 Oct 7;14(4):335-43
18835035
Clin Cancer Res. 2010 Jul 15;16(14):3721-33
20525753
J Biol Chem. 2007 May 11;282(19):14056-64
17360704
Crit Rev Oncol Hematol. 2007 Sep;63(3):215-30
17658267
Cell. 2000 Jan 7;100(1):57-70
10647931
Curr Opin Hematol. 2009 Mar;16(2):64-9
19468266
PLoS One. 2009;4(4):e5145
19357769
PLoS One. 2009 Jun 10;4(6):e5859
19516899
Cancer Treat Rev. 2010 Apr;36(2):142-50
20056334
Curr Opin Chem Biol. 2006 Feb;10(1):20-7
16406766
Curr Opin Hematol. 2009 Mar;16(2):98-104
19468271
Nature. 2006 May 25;441(7092):475-82
16598206
Ann N Y Acad Sci. 1993 Mar 20;677:265-80
8494214
Oncogene. 2000 May 15;19(21):2511-22
10851050
J Clin Invest. 2002 May;109(9):1139-42
11994401
Nat Rev Cancer. 2007 Dec;7(12):925-36
18004398
Blood. 2008 Feb 15;111(4):1903-12
18042804
Br J Haematol. 2003 Aug;122(3):454-6
12877673
Blood. 2005 Aug 15;106(4):1154-63
15870183
Clin Cancer Res. 2009 Jul 1;15(13):4263-9
19549778
Blood. 2006 Nov 1;108(9):3135-42
16835385
Nat Immunol. 2009 Apr;10(4):327-31
19295628
Blood. 2003 Apr 15;101(8):2940-54
12480704
J Leukoc Biol. 2009 Dec;86(6):1295-303
19801497
Nucleic Acids Res. 2008 Jun;36(11):3802-18
18492722
Nat Rev Cancer. 2006 Feb;6(2):146-55
16491074
Arthritis Res Ther. 2006;8 Suppl 2:S2
16899106
Clin Cancer Res. 2010 Jan 15;16(2):376-83
20068082