The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2022
2022
Historique:
received:
30
05
2022
accepted:
11
10
2022
entrez:
25
10
2022
pubmed:
26
10
2022
medline:
28
10
2022
Statut:
epublish
Résumé
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease with heterogeneous clinical course. Recent studies revealed a link between NOTCH1 mutation and the overexpression of MYC and MYC-related genes involved in ribosome biogenesis and protein biosynthesis, such as nucleophosmin-1 (NPM1), in CLL cells. In the present study, we aim to evaluate the impact of the NOTCH1 mutation on the MYC and MYC induced NPM1 expression in CLL cells via quantification of their transcripts. Using qRT-PCR, we analyzed the levels of MYC and three main NPM1 splice variants in 214 samples collected from CLL patients. We assessed the impact of each splice variant on CLL prognostic markers, including the IGHV, TP53, NOTCH1, SF3B1, and MYD88 mutational status, cytogenetic aberrations, and laboratory features. Significantly higher levels of NPM1.R1 transcripts in patients with unmutated compared to mutated IGHV status were found. The median time to first treatment (TTFT) in patients with a high level of NPM1.R1 was significantly shorter compared to the group with low NPM1.R1 levels (1.5 vs 33 months, p = 0.0002). Moreover, in Multivariate Cox Proportional Hazard Regression Model NPM1.R1 splice variant provided an independent prognostic value for TTFT. In conclusion, our study indicates the prognostic significance of the level of NPM1.R1 expression and suggests the importance of splicing alterations in the pathogenesis of CLL.
Identifiants
pubmed: 36282861
doi: 10.1371/journal.pone.0276674
pii: PONE-D-22-15632
pmc: PMC9595542
doi:
Substances chimiques
Myeloid Differentiation Factor 88
0
Nuclear Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0276674Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Cancer Cell. 2018 Sep 10;34(3):499-512.e9
pubmed: 30205049
Genome Med. 2015 May 15;7(1):45
pubmed: 26113877
Blood. 2012 Jan 12;119(2):521-9
pubmed: 22077063
Leukemia. 2017 Nov;31(11):2407-2415
pubmed: 28321119
Oncotarget. 2017 Aug 3;8(56):95163-95175
pubmed: 29221119
Leukemia. 2014 Jan;28(1):108-17
pubmed: 24113472
Pol Arch Intern Med. 2017 Apr 28;127(4):238-244
pubmed: 28424451
Blood. 2012 Apr 5;119(14):3203-10
pubmed: 22323480
PLoS One. 2014 May 05;9(5):e96293
pubmed: 24796332
Int J Hematol. 2019 Aug;110(2):150-160
pubmed: 30632059
J Cell Biol. 2016 Jan 4;212(1):13-27
pubmed: 26728853
Clin Cancer Res. 2014 Mar 1;20(5):1135-45
pubmed: 24284058
Haematologica. 2007 Apr;92(4):519-32
pubmed: 17488663
Nat Rev Cancer. 2008 Dec;8(12):976-90
pubmed: 19029958
Blood. 2014 May 22;123(21):3247-54
pubmed: 24652989
Immunol Lett. 2002 Aug 1;83(1):67-72
pubmed: 12057857
Cancer. 2019 May 1;125(9):1432-1440
pubmed: 30807655
BMC Mol Biol. 2016 Aug 24;17(1):19
pubmed: 27553022
Am J Clin Pathol. 2014 Mar;141(3):404-14
pubmed: 24515769
Front Oncol. 2018 Jun 27;8:229
pubmed: 29998084
Nature. 2011 Sep 11;478(7367):64-9
pubmed: 21909114
Int J Cancer. 2013 Oct 1;133(7):1567-77
pubmed: 23536448
JCI Insight. 2018 Oct 4;3(19):
pubmed: 30282833
Br J Haematol. 2010 Feb;148(4):534-43
pubmed: 19961478
Nat Genet. 2011 Dec 11;44(1):47-52
pubmed: 22158541
Cell Rep. 2017 Aug 29;20(9):2215-2226
pubmed: 28854369
Cancer Cell. 2016 Nov 14;30(5):750-763
pubmed: 27818134
Nat Rev Cancer. 2016 Mar;16(3):145-62
pubmed: 26911189
J Transl Med. 2018 Aug 20;16(1):232
pubmed: 30126426
Am J Hematol. 2019 Nov;94(11):1266-1287
pubmed: 31364186
Cancer Cell. 2019 Feb 11;35(2):283-296.e5
pubmed: 30712845