Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML.
Adult
Aged
Aged, 80 and over
Blood Proteins
/ metabolism
Cell Survival
/ drug effects
Cytokines
/ metabolism
Extracellular Signal-Regulated MAP Kinases
/ antagonists & inhibitors
Female
Humans
Leukemia, Myelomonocytic, Chronic
/ drug therapy
MAP Kinase Signaling System
/ drug effects
Male
Middle Aged
Monocytes
/ metabolism
Myeloid Cell Leukemia Sequence 1 Protein
/ antagonists & inhibitors
Protein Kinase Inhibitors
/ pharmacology
Xenograft Model Antitumor Assays
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
17 06 2021
17 06 2021
Historique:
received:
18
08
2020
accepted:
11
02
2021
pubmed:
11
3
2021
medline:
15
12
2021
entrez:
10
3
2021
Statut:
ppublish
Résumé
Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
Identifiants
pubmed: 33690800
pii: S0006-4971(21)00579-6
doi: 10.1182/blood.2020008729
pmc: PMC8233685
doi:
Substances chimiques
Blood Proteins
0
CYTL1 protein, human
0
Cytokines
0
MCL1 protein, human
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Protein Kinase Inhibitors
0
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3390-3402Subventions
Organisme : NCI NIH HHS
ID : R37 CA234021
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
Références
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3516-20
pubmed: 7682708
Nature. 2015 Sep 17;525(7569):389-393
pubmed: 26287468
Cell. 2012 Oct 12;151(2):344-55
pubmed: 23063124
Nature. 2010 Feb 18;463(7283):899-905
pubmed: 20164920
Blood. 2017 Jul 13;130(2):126-136
pubmed: 28572287
Blood. 2020 Aug 13;136(7):909-913
pubmed: 32294158
Blood. 2016 May 19;127(20):2391-405
pubmed: 27069254
Leukemia. 2020 Nov;34(11):2951-2963
pubmed: 32576961
Blood Adv. 2017 Jun 13;1(14):972-979
pubmed: 29296739
Cancer Cell. 2015 May 11;27(5):671-81
pubmed: 25965572
Sci Transl Med. 2017 Aug 2;9(401):
pubmed: 28768804
Database (Oxford). 2017 Jan 1;2017:
pubmed: 28605766
Cell Death Differ. 2017 Dec;24(12):2032-2043
pubmed: 28800129
Leukemia. 2016 May;30(5):1018-24
pubmed: 26854026
J Biol Chem. 2007 Oct 5;282(40):29359-67
pubmed: 17644814
Nature. 2016 Oct 27;538(7626):477-482
pubmed: 27760111
J Clin Invest. 2018 Dec 3;128(12):5479-5488
pubmed: 30252677
J Immunol. 2016 May 15;196(10):4090-9
pubmed: 27084102
Lancet Diabetes Endocrinol. 2015 Sep;3(9):687-96
pubmed: 26268910
Pharmacol Ther. 2019 Mar;195:13-20
pubmed: 30347215
Genomics. 2000 May 1;65(3):283-92
pubmed: 10857752
Cytokine. 2017 Aug;96:238-246
pubmed: 28478073
Lancet Oncol. 2016 May;17(5):651-62
pubmed: 27055731
Blood. 2017 Apr 6;129(14):1969-1979
pubmed: 28151428
Blood. 2001 Sep 1;98(5):1429-39
pubmed: 11520792
Nat Commun. 2018 Dec 21;9(1):5455
pubmed: 30575719
Nat Commun. 2016 Feb 24;7:10767
pubmed: 26908133
Blood. 2017 Jul 27;130(4):397-407
pubmed: 28576879
Blood. 2017 Mar 30;129(13):1753-1762
pubmed: 28096091
PLoS One. 2011;6(7):e22256
pubmed: 21799806
Blood Adv. 2019 Oct 22;3(20):2949-2961
pubmed: 31648319
Nat Rev Cancer. 2017 Jun 23;17(7):425-440
pubmed: 28642604
Cancer Cell. 2018 Dec 10;34(6):879-891
pubmed: 30537511
Nat Commun. 2017 Jul 17;8:16078
pubmed: 28714472
JCI Insight. 2018 Oct 4;3(19):
pubmed: 30282833
Cancer Cell. 2011 Nov 15;20(5):661-73
pubmed: 22094259
Blood. 2015 Jun 4;125(23):3618-26
pubmed: 25852055
Leukemia. 2019 Oct;33(10):2466-2480
pubmed: 30894665
Leukemia. 2019 Jan;33(1):205-216
pubmed: 30026572
J Acquir Immune Defic Syndr. 2018 Sep 1;79(1):108-116
pubmed: 29781885
Blood Cancer J. 2019 Jan 15;9(2):4
pubmed: 30647404
Cell Stem Cell. 2018 Dec 6;23(6):833-849.e5
pubmed: 30526882
Blood. 2013 Mar 21;121(12):2186-98
pubmed: 23319568
Cancer Cell. 2018 Jan 8;33(1):44-59.e8
pubmed: 29275866
Nat Commun. 2019 Apr 26;10(1):1935
pubmed: 31028249
J Clin Invest. 2017 Jan 3;127(1):153-168
pubmed: 27893461