Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia.
Journal
Blood cancer discovery
ISSN: 2643-3249
Titre abrégé: Blood Cancer Discov
Pays: United States
ID NLM: 101764786
Informations de publication
Date de publication:
06 09 2022
06 09 2022
Historique:
received:
18
10
2021
revised:
05
05
2022
accepted:
12
07
2022
pubmed:
16
7
2022
medline:
9
9
2022
entrez:
15
7
2022
Statut:
ppublish
Résumé
Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL. This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369.
Identifiants
pubmed: 35839275
pii: 707014
doi: 10.1158/2643-3230.BCD-21-0192
pmc: PMC9894574
doi:
Substances chimiques
Receptors, Erythropoietin
0
JAK2 protein, human
EC 2.7.10.2
Janus Kinase 2
EC 2.7.10.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
410-427Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
Références
Nature. 2021 Mar;591(7848):137-141
pubmed: 33361815
Cancer Cell. 2016 Feb 8;29(2):186-200
pubmed: 26859458
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3915-20
pubmed: 15007164
N Engl J Med. 2013 May 30;368(22):2059-74
pubmed: 23634996
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Blood. 2016 May 19;127(20):2391-405
pubmed: 27069254
Blood. 1989 Feb;73(2):375-80
pubmed: 2537111
Blood. 2021 Mar 25;137(12):1628-1640
pubmed: 33512458
Mod Pathol. 2011 Mar;24(3):375-83
pubmed: 21102413
Nature. 2019 May;569(7757):503-508
pubmed: 31068700
Blood Cancer J. 2017 Aug 25;7(8):e594
pubmed: 28841205
Br J Haematol. 1976 Aug;33(4):451-8
pubmed: 188440
Cancer Discov. 2019 Jul;9(7):910-925
pubmed: 31048320
Nature. 2020 Feb;578(7793):112-121
pubmed: 32025012
Blood. 2015 Feb 26;125(9):1367-76
pubmed: 25550361
Cancer Genet Cytogenet. 2005 Dec;163(2):113-22
pubmed: 16337853
Leukemia. 2016 Apr;30(4):966-70
pubmed: 26202927
Leukemia. 2017 Jan;31(1):195-202
pubmed: 27389056
Cell. 1993 Jul 30;74(2):227-36
pubmed: 8343951
Nat Commun. 2018 Sep 7;9(1):3649
pubmed: 30194306
Nat Genet. 2017 Feb;49(2):204-212
pubmed: 27992414
Genome Biol. 2014;15(12):550
pubmed: 25516281
J Clin Oncol. 1999 Dec;17(12):3835-49
pubmed: 10577857
Cancer Cell. 2016 Apr 11;29(4):574-586
pubmed: 27070704
Blood. 2017 May 4;129(18):2584-2587
pubmed: 28246192
Blood. 2002 Oct 1;100(7):2292-302
pubmed: 12239137
Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6091-6
pubmed: 23533276
Blood. 1952 Aug;7(8):765-93
pubmed: 14934762
Blood. 2002 Nov 1;100(9):3175-82
pubmed: 12384415
Eur J Haematol. 2011 Mar;86(3):206-15
pubmed: 21114538
Bioinformatics. 2011 Jan 15;27(2):268-9
pubmed: 21081509
Blood. 2014 May 29;123(22):3466-77
pubmed: 24637361
Leukemia. 1997 Nov;11(11):1941-9
pubmed: 9369430
Blood. 2017 Apr 27;129(17):2347-2358
pubmed: 28223278
Blood. 2020 Aug 6;136(6):698-714
pubmed: 32350520
Blood. 2013 Aug 8;122(6):988-98
pubmed: 23719302
N Engl J Med. 2016 Jun 9;374(23):2209-2221
pubmed: 27276561
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
Nature. 2018 Oct;562(7728):526-531
pubmed: 30333627
Nature. 2011 Sep 11;478(7367):64-9
pubmed: 21909114
Leukemia. 2014 Feb;28(2):241-7
pubmed: 24220272
Blood. 2019 Mar 7;133(10):1049-1059
pubmed: 30670442
Nat Genet. 2019 Apr;51(4):694-704
pubmed: 30926971
Blood. 2009 Jul 30;114(5):937-51
pubmed: 19357394
Nucleic Acids Res. 2013 Apr;41(7):e89
pubmed: 23471004
Blood. 2013 Nov 21;122(22):3616-27; quiz 3699
pubmed: 24030381
Leukemia. 2008 Mar;22(3):521-9
pubmed: 18094719
Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15437-42
pubmed: 22936051
Leukemia. 2013 Sep;27(9):1940-3
pubmed: 23648669
Proc Natl Acad Sci U S A. 2017 May 16;114(20):E4030-E4039
pubmed: 28461505
Nat Genet. 2015 Nov;47(11):1304-15
pubmed: 26437031
Blood Rev. 2018 Mar;32(2):96-105
pubmed: 28965757
Nature. 2016 May 23;534(7607):402-6
pubmed: 27281199
Nat Med. 2020 Oct;26(10):1549-1556
pubmed: 32747829
J Biol Chem. 1994 Jul 15;269(28):18291-4
pubmed: 8034573
J Am Chem Soc. 2015 Jun 24;137(24):7929-34
pubmed: 26042473
Br J Haematol. 1995 Aug;90(4):868-75
pubmed: 7669665