Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma
Abstract Diffuse large B cell lymphoma (DLBCL) is successfully treated with combination immuno-chemotherapy, but relapse with resistant disease occurs in ~ 40% of patients. However, little is known regarding relapsed/refractory DLBCL (rrDLBCL) genetics and alternative therapies. Based on findings fr...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-04736-0 |
| _version_ | 1819260974168801280 |
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| author | Alexandre Benoit Elisabeth Bou-Petit Hsiang Chou Melissa Lu Cynthia Guilbert Vincent Mingyi Luo Sarit Assouline Ryan D. Morin Svetlana Dmitrienko Roger Estrada-Tejedor Nathalie A. Johnson Koren K. Mann |
| author_facet | Alexandre Benoit Elisabeth Bou-Petit Hsiang Chou Melissa Lu Cynthia Guilbert Vincent Mingyi Luo Sarit Assouline Ryan D. Morin Svetlana Dmitrienko Roger Estrada-Tejedor Nathalie A. Johnson Koren K. Mann |
| author_sort | Alexandre Benoit |
| collection | DOAJ |
| description | Abstract Diffuse large B cell lymphoma (DLBCL) is successfully treated with combination immuno-chemotherapy, but relapse with resistant disease occurs in ~ 40% of patients. However, little is known regarding relapsed/refractory DLBCL (rrDLBCL) genetics and alternative therapies. Based on findings from other tumors, we hypothesized that RAS-MEK-ERK signaling would be upregulated in resistant tumors, potentially correlating with mutations in RAS, RAF, or associated proteins. We analyzed mutations and phospho-ERK levels in tumor samples from rrDLBCL patients. Unlike other tumor types, rrDLBCL is not mutated in any Ras or Raf family members, despite having increased expression of p-ERK. In paired biopsies comparing diagnostic and relapsed specimens, 33% of tumors gained p-ERK expression, suggesting a role in promoting survival. We did find mutations in several Ras-associating proteins, including GEFs, GAPs, and downstream effectors that could account for increased ERK activation. We further investigated mutations in one such protein, RASGRP4. In silico modeling indicated an increased interaction between H-Ras and mutant RASGRP4. In cell lines, mutant RASGRP4 increased basal p-ERK expression and lead to a growth advantage in colony forming assays when challenged with doxorubicin. Relapsed/refractory DLBCL is often associated with increased survival signals downstream of ERK, potentially corresponding with mutations in protein controlling RAS/MEK/ERK signaling. |
| first_indexed | 2024-12-23T19:34:25Z |
| format | Article |
| id | doaj.art-4fffe71040f44cc9b5dac6235bfe475e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-23T19:34:25Z |
| publishDate | 2022-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-4fffe71040f44cc9b5dac6235bfe475e2022-12-21T17:33:50ZengNature PortfolioScientific Reports2045-23222022-01-0112111310.1038/s41598-021-04736-0Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphomaAlexandre Benoit0Elisabeth Bou-Petit1Hsiang Chou2Melissa Lu3Cynthia Guilbert4Vincent Mingyi Luo5Sarit Assouline6Ryan D. Morin7Svetlana Dmitrienko8Roger Estrada-Tejedor9Nathalie A. Johnson10Koren K. Mann11Lady Davis Institute, Jewish General HospitalGrup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon LlullLady Davis Institute, Jewish General HospitalUniversité de Montréal-Faculté de MédecineLady Davis Institute, Jewish General HospitalLady Davis Institute, Jewish General HospitalLady Davis Institute, Jewish General HospitalDepartment of Molecular Biology and Biochemistry, Simon Fraser UniversityDivision of Pathology, McGill University Health CentreGrup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon LlullLady Davis Institute, Jewish General HospitalLady Davis Institute, Jewish General HospitalAbstract Diffuse large B cell lymphoma (DLBCL) is successfully treated with combination immuno-chemotherapy, but relapse with resistant disease occurs in ~ 40% of patients. However, little is known regarding relapsed/refractory DLBCL (rrDLBCL) genetics and alternative therapies. Based on findings from other tumors, we hypothesized that RAS-MEK-ERK signaling would be upregulated in resistant tumors, potentially correlating with mutations in RAS, RAF, or associated proteins. We analyzed mutations and phospho-ERK levels in tumor samples from rrDLBCL patients. Unlike other tumor types, rrDLBCL is not mutated in any Ras or Raf family members, despite having increased expression of p-ERK. In paired biopsies comparing diagnostic and relapsed specimens, 33% of tumors gained p-ERK expression, suggesting a role in promoting survival. We did find mutations in several Ras-associating proteins, including GEFs, GAPs, and downstream effectors that could account for increased ERK activation. We further investigated mutations in one such protein, RASGRP4. In silico modeling indicated an increased interaction between H-Ras and mutant RASGRP4. In cell lines, mutant RASGRP4 increased basal p-ERK expression and lead to a growth advantage in colony forming assays when challenged with doxorubicin. Relapsed/refractory DLBCL is often associated with increased survival signals downstream of ERK, potentially corresponding with mutations in protein controlling RAS/MEK/ERK signaling.https://doi.org/10.1038/s41598-021-04736-0 |
| spellingShingle | Alexandre Benoit Elisabeth Bou-Petit Hsiang Chou Melissa Lu Cynthia Guilbert Vincent Mingyi Luo Sarit Assouline Ryan D. Morin Svetlana Dmitrienko Roger Estrada-Tejedor Nathalie A. Johnson Koren K. Mann Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma Scientific Reports |
| title | Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma |
| title_full | Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma |
| title_fullStr | Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma |
| title_full_unstemmed | Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma |
| title_short | Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma |
| title_sort | mutated ras associating proteins and erk activation in relapse refractory diffuse large b cell lymphoma |
| url | https://doi.org/10.1038/s41598-021-04736-0 |
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