Phospho-Profiling Linking Biology and Clinics in Pediatric Acute Myeloid Leukemia.
Journal
HemaSphere
ISSN: 2572-9241
Titre abrégé: Hemasphere
Pays: United States
ID NLM: 101740619
Informations de publication
Date de publication:
Feb 2020
Feb 2020
Historique:
received:
27
06
2019
revised:
15
10
2019
accepted:
15
10
2019
entrez:
20
2
2020
pubmed:
20
2
2020
medline:
20
2
2020
Statut:
epublish
Résumé
Aberrant activation of key signaling-molecules is a hallmark of acute myeloid leukemia (AML) and may have prognostic and therapeutic implications. AML summarizes several disease entities with a variety of genetic subtypes. A comprehensive model spanning from signal activation patterns in major genetic subtypes of pediatric AML (pedAML) to outcome prediction and pre-clinical response to signaling inhibitors has not yet been provided. We established a high-throughput flow-cytometry based method to assess activation of hallmark phospho-proteins (phospho-flow) in 166 bone-marrow derived pedAML samples under basal and cytokine stimulated conditions. We correlated levels of activated phospho-proteins at diagnosis with relapse incidence in intermediate (IR) and high risk (HR) subtypes. In parallel, we screened a set of signaling inhibitors for their efficacy against primary AML blasts in a flow-cytometry based ex vivo cytotoxicity assay and validated the results in a murine xenograft model. Certain phospho-signal patterns differ between genetic subtypes of pedAML. Some are consistently seen through all AML subtypes such as pSTAT5. In IR/HR subtypes high levels of GM-CSF stimulated pSTAT5 and low levels of unstimulated pJNK correlated with increased relapse risk overall. Combination of GM-CSF/pSTAT5
Identifiants
pubmed: 32072137
doi: 10.1097/HS9.0000000000000312
pii: HemaSphere-2019-0138
pmc: PMC7000467
doi:
Types de publication
Journal Article
Langues
eng
Pagination
e312Informations de copyright
Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.
Déclaration de conflit d'intérêts
DR has a consulting or advisory role for Celgene, Roche, Hexal, Medac, Boehringer, Behring and Novartis and received research support from Celgene Roche, Behring and Novartis. DR also received payments for travel, accommodation or other expenses from JAZZ Pharmaceuticals. KN received payments for travel, accommodation or other expenses from Affymetrix. MND received honoraria as well as payments for travel, accommodation or other expenses from Beckman-Coulter. For the remaining authors, no relevant conflicts of interest were declared.
Références
Blood. 2014 May 1;123(18):2826-37
pubmed: 24668492
Blood. 1998 Feb 15;91(4):1101-34
pubmed: 9454740
Mol Cancer Ther. 2017 Jun;16(6):991-1001
pubmed: 28576946
N Engl J Med. 2006 May 11;354(19):2034-45
pubmed: 16687716
Leukemia. 2014 Mar;28(3):589-99
pubmed: 24240200
Haematologica. 2006 Jun;91(6):757-64
pubmed: 16769577
J Clin Oncol. 2010 Oct 1;28(28):4339-45
pubmed: 20733134
Leukemia. 2009 Jun;23(6):1029-38
pubmed: 19158829
Blood. 2016 May 19;127(20):2391-405
pubmed: 27069254
Blood. 2006 Oct 1;108(7):2358-65
pubmed: 16763210
Drug Discov Today Technol. 2017 Mar;23:45-52
pubmed: 28647085
N Engl J Med. 2017 Aug 3;377(5):454-464
pubmed: 28644114
Clin Cancer Res. 2014 Jan 15;20(2):490-8
pubmed: 24178622
Leukemia. 2003 May;17(5):995-7
pubmed: 12750723
Cell. 2004 Jul 23;118(2):217-28
pubmed: 15260991
Lancet Oncol. 2015 Dec;16(16):1691-9
pubmed: 26549589
Blood. 2003 Jun 15;101(12):4667-79
pubmed: 12623839
Haematologica. 2016 Jan;101(1):20-5
pubmed: 26721801
Leukemia. 2003 Sep;17(9):1783-93
pubmed: 12970778
Blood. 1996 Dec 15;88(12):4493-9
pubmed: 8977241
Leukemia. 2003 Jul;17(7):1263-93
pubmed: 12835716
Nat Rev Cancer. 2010 Feb;10(2):130-7
pubmed: 20094047
Blood. 2013 Feb 14;121(7):1083-93
pubmed: 23243289
Leukemia. 2009 Apr;23(4):791-3
pubmed: 18830265
Blood. 2012 Oct 18;120(16):3187-205
pubmed: 22879540
Eur Cytokine Netw. 2001 Apr-Jun;12(2):231-8
pubmed: 11399510
Leukemia. 2014 Mar;28(3):716-9
pubmed: 24247654
Stat Methods Med Res. 2016 Aug;25(4):1692-706
pubmed: 23907781
N Engl J Med. 2016 Jun 9;374(23):2209-2221
pubmed: 27276561
Leukemia. 2004 Jan;18(1):103-12
pubmed: 14574326
Stat Med. 1996 Dec 15;15(23):2589-601
pubmed: 8961465
J Cell Biochem. 2016 Aug;117(8):1745-52
pubmed: 27018341
Br J Haematol. 1996 Mar;92(4):907-12
pubmed: 8616084
Memo. 2014;7(1):63-74
pubmed: 32288851
Oncogene. 2002 May 13;21(21):3334-58
pubmed: 12032773
Drug Discov Today. 2013 Nov;18(21-22):1067-73
pubmed: 23850704
Cancer Cell. 2008 Oct 7;14(4):335-43
pubmed: 18835035
Curr Opin Hematol. 2017 Mar;24(2):99-107
pubmed: 28030373
Leukemia. 2001 Dec;15(12):1923-31
pubmed: 11753614
J Clin Oncol. 2011 Feb 10;29(5):475-86
pubmed: 21220609
Leukemia. 2005 Sep;19(9):1543-9
pubmed: 16001087
J Clin Oncol. 2011 Jul 10;29(20):2758-65
pubmed: 21632498
Leukemia. 2003 Mar;17(3):590-603
pubmed: 12646949
J Clin Oncol. 2015 Sep 20;33(27):2949-62
pubmed: 26304895
Nat Med. 2017 Sep 8;23(9):1028-1035
pubmed: 28886003
Eur J Haematol. 2001 Aug;67(2):63-71
pubmed: 11722592
Cancer Res. 2016 Mar 1;76(5):1214-24
pubmed: 26833125
Leukemia. 2018 Oct;32(10):2167-2177
pubmed: 29550834