Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia.
Actin Cytoskeleton
/ chemistry
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Bridged Bicyclo Compounds, Heterocyclic
/ pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Mutation
Proto-Oncogene Proteins c-bcl-2
/ antagonists & inhibitors
Pyrones
/ pharmacology
Quinolines
/ pharmacology
Staurosporine
/ analogs & derivatives
Sulfonamides
/ pharmacology
fms-Like Tyrosine Kinase 3
/ antagonists & inhibitors
rac1 GTP-Binding Protein
/ antagonists & inhibitors
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
25 06 2021
25 06 2021
Historique:
received:
20
10
2020
accepted:
07
05
2021
entrez:
26
6
2021
pubmed:
27
6
2021
medline:
17
8
2021
Statut:
epublish
Résumé
The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.
Identifiants
pubmed: 34172833
doi: 10.1038/s42003-021-02215-w
pii: 10.1038/s42003-021-02215-w
pmc: PMC8233337
doi:
Substances chimiques
Antineoplastic Agents
0
BCL2 protein, human
0
Bridged Bicyclo Compounds, Heterocyclic
0
EHT 1864
0
Proto-Oncogene Proteins c-bcl-2
0
Pyrones
0
Quinolines
0
RAC1 protein, human
0
Sulfonamides
0
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
rac1 GTP-Binding Protein
EC 3.6.5.2
Staurosporine
H88EPA0A3N
midostaurin
ID912S5VON
venetoclax
N54AIC43PW
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
799Références
World J Clin Oncol. 2011 Feb 10;2(2):80-93
pubmed: 21603317
Bioarchitecture. 2012 May 1;2(3):75-87
pubmed: 22880146
Clin Cancer Res. 2019 Nov 15;25(22):6815-6826
pubmed: 31320594
Biomaterials. 2014 Jul;35(22):5749-59
pubmed: 24726537
Clin Adv Hematol Oncol. 2013;11(9):586-8
pubmed: 24518522
J Biochem. 2007 Mar;141(3):319-25
pubmed: 17202194
Nature. 2010 Jan 28;463(7280):485-92
pubmed: 20110992
Leukemia. 2019 Aug;33(8):2098-2102
pubmed: 30816329
Sci Rep. 2017 Apr 10;7:46152
pubmed: 28393890
J Cell Sci. 2001 May;114(Pt 10):1801-9
pubmed: 11329366
Mol Cell. 2001 Sep;8(3):705-11
pubmed: 11583631
Cancer Res. 2017 Jan 15;77(2):434-447
pubmed: 27872092
Biochem Biophys Res Commun. 2017 Jan 22;482(4):1353-1359
pubmed: 27939884
Genes Dev. 1997 Sep 15;11(18):2295-322
pubmed: 9308960
J Cell Biol. 2000 Sep 4;150(5):1001-12
pubmed: 10973991
Br J Haematol. 2007 Sep;138(6):687-99
pubmed: 17655729
Haematologica. 2019 Dec;104(12):2418-2428
pubmed: 30975911
Biotechnol Bioeng. 2014 Feb;111(2):396-403
pubmed: 24018833
J Biol Chem. 2007 Dec 7;282(49):35666-78
pubmed: 17932039
Nanomedicine. 2012 Jul;8(5):757-66
pubmed: 22024198
Blood. 2003 Oct 15;102(8):2969-75
pubmed: 12842996
Cancer Cell. 2016 Jul 11;30(1):43-58
pubmed: 27344946
Small GTPases. 2015;6(2):71-80
pubmed: 25942647
J Am Chem Soc. 2017 Sep 13;139(36):12406-12409
pubmed: 28862842
Blood. 2011 Jun 9;117(23):6214-26
pubmed: 21474673
Sci Rep. 2015 Jun 29;5:11702
pubmed: 26118648
Oncotarget. 2018 Feb 5;9(16):12842-12852
pubmed: 29560114
Nat Methods. 2012 Nov;9(11):1040-1
pubmed: 23132113
Blood. 2004 May 15;103(10):3669-76
pubmed: 14726387
Blood. 2012 Oct 11;120(15):3069-79
pubmed: 22927251
Nature. 1990 Sep 6;347(6288):44-9
pubmed: 2395461
Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):E472-9
pubmed: 21676863
Cancer Cell. 2002 Jun;1(5):433-43
pubmed: 12124173
Crit Rev Oncol Hematol. 2018 Apr;124:29-36
pubmed: 29548483
Small GTPases. 2014;5:e27958
pubmed: 24607953
J Hematol Oncol. 2009 Jul 30;2:33
pubmed: 19642998
Nature. 2012 Apr 15;485(7397):260-3
pubmed: 22504184
Blood. 2006 Nov 15;108(10):3477-83
pubmed: 16857987
Database (Oxford). 2015 Feb 27;2015:
pubmed: 25725062
Sci Rep. 2019 May 22;9(1):7675
pubmed: 31118438
Mol Cell. 2003 May;11(5):1229-39
pubmed: 12769847
Nature. 1990 Sep 6;347(6288):95-9
pubmed: 2168523
Blood. 2009 Jul 16;114(3):619-29
pubmed: 19443661
Oncogene. 2018 Dec;37(50):6425-6441
pubmed: 30065298
Oncotarget. 2016 Apr 5;7(14):17970-85
pubmed: 26918455
Cancer Res. 2018 Oct 1;78(19):5631-5643
pubmed: 30104240
Leukemia. 2019 Apr;33(4):905-917
pubmed: 30214012
Cell Rep. 2014 Nov 20;9(4):1333-48
pubmed: 25456130
Cancer Sci. 2018 Sep;109(9):2706-2716
pubmed: 29945297
Clin Cancer Res. 2003 Jun;9(6):2140-50
pubmed: 12796379
Biochemistry. 2007 Mar 20;46(11):3494-502
pubmed: 17302440
Nano Lett. 2009 Jun;9(6):2501-7
pubmed: 19453133
Chem Biol. 2010 Nov 24;17(11):1241-9
pubmed: 21095574