AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL
Adaptive somatic mutations conferring treatment resistance and accelerated disease progression is still a major problem in cancer therapy. Additionally in CLL, patients receiving novel, efficient drugs frequently become treatment refractory and eventually relapse. Activation-induced deaminase (AID)...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/11/2619 |
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| author | Maria Schubert Franz Josef Gassner Michael Huemer Jan Philip Höpner Ekaterina Akimova Markus Steiner Alexander Egle Richard Greil Nadja Zaborsky Roland Geisberger |
| author_facet | Maria Schubert Franz Josef Gassner Michael Huemer Jan Philip Höpner Ekaterina Akimova Markus Steiner Alexander Egle Richard Greil Nadja Zaborsky Roland Geisberger |
| author_sort | Maria Schubert |
| collection | DOAJ |
| description | Adaptive somatic mutations conferring treatment resistance and accelerated disease progression is still a major problem in cancer therapy. Additionally in CLL, patients receiving novel, efficient drugs frequently become treatment refractory and eventually relapse. Activation-induced deaminase (AID) is a cytosine deaminase that catalyzes somatic hypermutation of genomic DNA at the immunoglobulin locus in activated B cells. As considerable off-target mutations by AID have been discerned in chronic lymphocytic leukemia, it is essential to investigate to which extent these mutations contribute to disease progression to estimate whether AID inhibition could counteract drug resistance mechanisms. In this study, we examined the TCL1 mouse model for CLL on an AID pro- and deficient background by comparing disease development and mutational landscapes. We provide evidence that AID contributes to the acquisition of somatic cancer-specific mutations also in the TCL1 model and accelerates CLL development particularly in the transplant setting. We conclude that AID is directly determining the fitness of the CLL clone, which prompts further studies to assess the effect of AID inhibition on the occurrence of drug resistance. |
| first_indexed | 2024-03-10T11:01:58Z |
| format | Article |
| id | doaj.art-f19a55c2b253489793c26462c92fdef6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:01:58Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-f19a55c2b253489793c26462c92fdef62023-11-21T21:30:06ZengMDPI AGCancers2072-66942021-05-011311261910.3390/cancers13112619AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLLMaria Schubert0Franz Josef Gassner1Michael Huemer2Jan Philip Höpner3Ekaterina Akimova4Markus Steiner5Alexander Egle6Richard Greil7Nadja Zaborsky8Roland Geisberger9Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, AustriaAdaptive somatic mutations conferring treatment resistance and accelerated disease progression is still a major problem in cancer therapy. Additionally in CLL, patients receiving novel, efficient drugs frequently become treatment refractory and eventually relapse. Activation-induced deaminase (AID) is a cytosine deaminase that catalyzes somatic hypermutation of genomic DNA at the immunoglobulin locus in activated B cells. As considerable off-target mutations by AID have been discerned in chronic lymphocytic leukemia, it is essential to investigate to which extent these mutations contribute to disease progression to estimate whether AID inhibition could counteract drug resistance mechanisms. In this study, we examined the TCL1 mouse model for CLL on an AID pro- and deficient background by comparing disease development and mutational landscapes. We provide evidence that AID contributes to the acquisition of somatic cancer-specific mutations also in the TCL1 model and accelerates CLL development particularly in the transplant setting. We conclude that AID is directly determining the fitness of the CLL clone, which prompts further studies to assess the effect of AID inhibition on the occurrence of drug resistance.https://www.mdpi.com/2072-6694/13/11/2619activation induced deaminase (AID)CLLclonal evolutiondeaminasedrug resistance |
| spellingShingle | Maria Schubert Franz Josef Gassner Michael Huemer Jan Philip Höpner Ekaterina Akimova Markus Steiner Alexander Egle Richard Greil Nadja Zaborsky Roland Geisberger AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL Cancers activation induced deaminase (AID) CLL clonal evolution deaminase drug resistance |
| title | AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL |
| title_full | AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL |
| title_fullStr | AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL |
| title_full_unstemmed | AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL |
| title_short | AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL |
| title_sort | aid contributes to accelerated disease progression in the tcl1 mouse transplant model for cll |
| topic | activation induced deaminase (AID) CLL clonal evolution deaminase drug resistance |
| url | https://www.mdpi.com/2072-6694/13/11/2619 |
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