Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia.
Animals
Bone Marrow Transplantation
Carcinogenesis
/ genetics
Disease Models, Animal
Female
GTP Phosphohydrolases
/ genetics
HEK293 Cells
Humans
Membrane Proteins
/ genetics
Mice
Mice, Inbred C57BL
Mutation
Oncogene Proteins, Fusion
/ genetics
Oncogenes
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
Proto-Oncogene Mas
Proto-Oncogene Proteins
/ genetics
T Cell Transcription Factor 1
/ genetics
T-Lymphocytes
/ metabolism
Trans-Activators
/ genetics
Transcriptome
beta Catenin
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 07 2021
06 07 2021
Historique:
received:
08
04
2020
accepted:
18
06
2021
entrez:
7
7
2021
pubmed:
8
7
2021
medline:
27
7
2021
Statut:
epublish
Résumé
Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.
Identifiants
pubmed: 34230493
doi: 10.1038/s41467-021-24442-9
pii: 10.1038/s41467-021-24442-9
pmc: PMC8260768
doi:
Substances chimiques
MAS1 protein, human
0
Membrane Proteins
0
Oncogene Proteins, Fusion
0
Proto-Oncogene Mas
0
Proto-Oncogene Proteins
0
T Cell Transcription Factor 1
0
TCF7 protein, human
0
Trans-Activators
0
beta Catenin
0
proto-oncogene protein Spi-1
0
GTP Phosphohydrolases
EC 3.6.1.-
NRAS protein, human
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4164Références
J Hematol Oncol. 2012 May 08;5:22
pubmed: 22569057
Development. 1999 Jun;126(14):3131-48
pubmed: 10375504
Gigascience. 2018 Jul 1;7(7):
pubmed: 30010766
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cell Rep. 2013 Dec 26;5(6):1704-13
pubmed: 24332856
Science. 2020 Feb 21;367(6480):
pubmed: 32079746
Nature. 2011 Aug 03;476(7358):63-8
pubmed: 21814277
PLoS Med. 2016 Dec 20;13(12):e1002200
pubmed: 27997540
Nucleic Acids Res. 2012 Aug;40(15):e114
pubmed: 22718975
J Biol Chem. 1992 Apr 25;267(12):8530-6
pubmed: 1569101
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Leukemia. 2015 May;29(5):1032-40
pubmed: 25371176
Science. 1997 Mar 21;275(5307):1790-2
pubmed: 9065403
Nat Rev Cancer. 2003 Jan;3(1):11-22
pubmed: 12509763
J Immunol Methods. 2009 Aug 15;347(1-2):70-8
pubmed: 19567251
Blood. 2014 Nov 13;124(20):3092-100
pubmed: 25193870
Cancer Cell. 2017 Nov 13;32(5):552-560
pubmed: 29136503
Nat Genet. 2006 Jan;38(1):27-37
pubmed: 16311598
Genome Res. 2021 Mar;31(3):448-460
pubmed: 33441414
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
Nat Genet. 2004 Jun;36(6):624-30
pubmed: 15146183
Blood. 2017 Mar 2;129(9):1113-1123
pubmed: 28115373
Leukemia. 2018 Jun;32(6):1358-1369
pubmed: 29740158
Nat Commun. 2019 Jul 16;10(1):3120
pubmed: 31311926
Genome Biol. 2019 Dec 23;20(1):296
pubmed: 31870423
Nat Genet. 2017 Aug;49(8):1274-1281
pubmed: 28671687
Genome Res. 2017 May;27(5):737-746
pubmed: 28100585
Nat Genet. 2017 Aug;49(8):1211-1218
pubmed: 28671688
Nat Methods. 2019 Dec;16(12):1289-1296
pubmed: 31740819
Nature. 2008 May 22;453(7194):529-33
pubmed: 18463637
Genome Biol. 2019 Mar 22;20(1):63
pubmed: 30902100
Cancer Discov. 2018 May;8(5):616-631
pubmed: 29496663
Cancer Treat Rev. 2018 Jan;62:50-60
pubmed: 29169144
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1486-91
pubmed: 16432184
Elife. 2018 Nov 09;7:
pubmed: 30412053
Mol Cell Biol. 1993 May;13(5):2929-41
pubmed: 8474451
Blood. 2011 Jul 14;118(2):368-79
pubmed: 21586752
Eur J Immunol. 2015 Mar;45(3):932-42
pubmed: 25408420
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
Nature. 1988 Jan 21;331(6153):277-80
pubmed: 2827041
Genome Res. 2017 May;27(5):722-736
pubmed: 28298431
Nat Biotechnol. 2018 Jun;36(5):411-420
pubmed: 29608179
Nat Genet. 2013 Feb;45(2):186-90
pubmed: 23263491
Genome Res. 2013 Dec;23(12):2115-25
pubmed: 24056532
Nat Biotechnol. 2018 Dec 03;:
pubmed: 30531897
Cancer Cell. 2019 Dec 9;36(6):630-644.e9
pubmed: 31735627
Cancer Cell. 2018 Aug 13;34(2):271-285.e7
pubmed: 30107177
EMBO Mol Med. 2021 Mar 5;13(3):e12670
pubmed: 33555144
Chem Biol. 2010 Jun 25;17(6):646-57
pubmed: 20609414
Nat Genet. 2006 Nov;38(11):1269-77
pubmed: 17041602
Nat Rev Immunol. 2014 Aug;14(8):529-45
pubmed: 25060579
Genome Biol. 2016 Feb 17;17:29
pubmed: 26887813
Nature. 1995 Mar 2;374(6517):70-4
pubmed: 7870176
Nat Cancer. 2021 Mar;2(3):284-299
pubmed: 34151288
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Cancer Discov. 2019 Jun;9(6):796-811
pubmed: 31018969
Leukemia. 2018 Apr;32(4):941-951
pubmed: 29151585
Leukemia. 2004 Apr;18(4):685-92
pubmed: 14990973
Cell. 2012 Mar 2;148(5):886-95
pubmed: 22385958
Development. 2013 Mar;140(6):1207-19
pubmed: 23444353
Cell. 2019 Jun 13;177(7):1888-1902.e21
pubmed: 31178118
Blood. 2019 Oct 17;134(16):1323-1336
pubmed: 31492675
Immunity. 2002 Feb;16(2):285-96
pubmed: 11869688
Blood. 2002 Aug 1;100(3):998-1007
pubmed: 12130514
Immunity. 2018 Feb 20;48(2):243-257.e10
pubmed: 29466756
Bioinformatics. 2018 Sep 15;34(18):3094-3100
pubmed: 29750242
Nat Commun. 2017 Jan 16;8:14049
pubmed: 28091601
J Cell Mol Med. 2009 Nov-Dec;13(11-12):4349-63
pubmed: 19382896
Science. 2014 Dec 12;346(6215):1373-7
pubmed: 25394790
Blood. 1991 Mar 15;77(6):1218-27
pubmed: 1705833
PLoS Genet. 2013;9(12):e1003997
pubmed: 24367274
Cell. 2017 Jun 1;169(6):985-999
pubmed: 28575679
Nature. 2012 Jan 11;481(7380):157-63
pubmed: 22237106