The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia.
<h4>Objectives</h4>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,...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0276674 |
| _version_ | 1811192485474467840 |
|---|---|
| author | Monika Szelest Marta Masternak Małgorzata Zając Michał Chojnacki Katarzyna Skórka Joanna Zaleska Agnieszka Karczmarczyk Grażyna Stasiak Ewa Wawrzyniak Aleksandra Kotkowska Monika Siemieniuk-Ryś Joanna Purkot Edyta Subocz Edyta Cichocka Waldemar Tomczak Daria Zawirska Krzysztof Giannopoulos |
| author_facet | Monika Szelest Marta Masternak Małgorzata Zając Michał Chojnacki Katarzyna Skórka Joanna Zaleska Agnieszka Karczmarczyk Grażyna Stasiak Ewa Wawrzyniak Aleksandra Kotkowska Monika Siemieniuk-Ryś Joanna Purkot Edyta Subocz Edyta Cichocka Waldemar Tomczak Daria Zawirska Krzysztof Giannopoulos |
| author_sort | Monika Szelest |
| collection | DOAJ |
| description | <h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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. |
| first_indexed | 2024-04-11T23:53:22Z |
| format | Article |
| id | doaj.art-c090ad7b145c4387b17bc511ab417c17 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-11T23:53:22Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c090ad7b145c4387b17bc511ab417c172022-12-22T03:56:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-011710e027667410.1371/journal.pone.0276674The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia.Monika SzelestMarta MasternakMałgorzata ZającMichał ChojnackiKatarzyna SkórkaJoanna ZaleskaAgnieszka KarczmarczykGrażyna StasiakEwa WawrzyniakAleksandra KotkowskaMonika Siemieniuk-RyśJoanna PurkotEdyta SuboczEdyta CichockaWaldemar TomczakDaria ZawirskaKrzysztof Giannopoulos<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.https://doi.org/10.1371/journal.pone.0276674 |
| spellingShingle | Monika Szelest Marta Masternak Małgorzata Zając Michał Chojnacki Katarzyna Skórka Joanna Zaleska Agnieszka Karczmarczyk Grażyna Stasiak Ewa Wawrzyniak Aleksandra Kotkowska Monika Siemieniuk-Ryś Joanna Purkot Edyta Subocz Edyta Cichocka Waldemar Tomczak Daria Zawirska Krzysztof Giannopoulos The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia. PLoS ONE |
| title | The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia. |
| title_full | The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia. |
| title_fullStr | The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia. |
| title_full_unstemmed | The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia. |
| title_short | The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia. |
| title_sort | role of npm1 alternative splicing in patients with chronic lymphocytic leukemia |
| url | https://doi.org/10.1371/journal.pone.0276674 |
| work_keys_str_mv | AT monikaszelest theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT martamasternak theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT małgorzatazajac theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT michałchojnacki theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT katarzynaskorka theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT joannazaleska theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT agnieszkakarczmarczyk theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT grazynastasiak theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT ewawawrzyniak theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT aleksandrakotkowska theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT monikasiemieniukrys theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT joannapurkot theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT edytasubocz theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT edytacichocka theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT waldemartomczak theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT dariazawirska theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT krzysztofgiannopoulos theroleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT monikaszelest roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT martamasternak roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT małgorzatazajac roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT michałchojnacki roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT katarzynaskorka roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT joannazaleska roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT agnieszkakarczmarczyk roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT grazynastasiak roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT ewawawrzyniak roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT aleksandrakotkowska roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT monikasiemieniukrys roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT joannapurkot roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT edytasubocz roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT edytacichocka roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT waldemartomczak roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT dariazawirska roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia AT krzysztofgiannopoulos roleofnpm1alternativesplicinginpatientswithchroniclymphocyticleukemia |