Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients
Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission ha...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-12-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/12/3738 |
| _version_ | 1797544960249036800 |
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| author | Ulf Schmitz Jaynish S. Shah Bijay P. Dhungel Geoffray Monteuuis Phuc-Loi Luu Veronika Petrova Cynthia Metierre Shalima S. Nair Charles G. Bailey Verity A. Saunders Ali G. Turhan Deborah L. White Susan Branford Susan J. Clark Timothy P. Hughes Justin J.-L. Wong John E.J. Rasko |
| author_facet | Ulf Schmitz Jaynish S. Shah Bijay P. Dhungel Geoffray Monteuuis Phuc-Loi Luu Veronika Petrova Cynthia Metierre Shalima S. Nair Charles G. Bailey Verity A. Saunders Ali G. Turhan Deborah L. White Susan Branford Susan J. Clark Timothy P. Hughes Justin J.-L. Wong John E.J. Rasko |
| author_sort | Ulf Schmitz |
| collection | DOAJ |
| description | Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease. |
| first_indexed | 2024-03-10T14:07:51Z |
| format | Article |
| id | doaj.art-7f9c37c705da45f193de8536d3cea524 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T14:07:51Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-7f9c37c705da45f193de8536d3cea5242023-11-21T00:28:50ZengMDPI AGCancers2072-66942020-12-011212373810.3390/cancers12123738Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia PatientsUlf Schmitz0Jaynish S. Shah1Bijay P. Dhungel2Geoffray Monteuuis3Phuc-Loi Luu4Veronika Petrova5Cynthia Metierre6Shalima S. Nair7Charles G. Bailey8Verity A. Saunders9Ali G. Turhan10Deborah L. White11Susan Branford12Susan J. Clark13Timothy P. Hughes14Justin J.-L. Wong15John E.J. Rasko16Computational BioMedicine Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW 2050, AustraliaGene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW 2050, AustraliaGene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW 2050, AustraliaGene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW 2050, AustraliaEpigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, AustraliaComputational BioMedicine Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW 2050, AustraliaGene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW 2050, AustraliaKinghorn Centre for Clinical Genomics Core Facility, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, AustraliaGene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW 2050, AustraliaCancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute, Adelaide, SA 50000, AustraliaAPHP, Division of Hematology, Paris Sud University Hospitals and Inserm U935 INGESTEM Pluripotent Stem Cell Infrastructure 78 Rue du Général Leclerc, 94275 Le Kremlin Bicetre, FranceCancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute, Adelaide, SA 50000, AustraliaSchool of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, AustraliaEpigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, AustraliaSchool of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, AustraliaFaculty of Medicine & Health, The University of Sydney, Camperdown, NSW 2050, AustraliaGene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW 2050, AustraliaVast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.https://www.mdpi.com/2072-6694/12/12/3738transcriptomic complexityalternative splicingintron retentionDNA methylationepigeneticsBCR-ABL1 |
| spellingShingle | Ulf Schmitz Jaynish S. Shah Bijay P. Dhungel Geoffray Monteuuis Phuc-Loi Luu Veronika Petrova Cynthia Metierre Shalima S. Nair Charles G. Bailey Verity A. Saunders Ali G. Turhan Deborah L. White Susan Branford Susan J. Clark Timothy P. Hughes Justin J.-L. Wong John E.J. Rasko Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients Cancers transcriptomic complexity alternative splicing intron retention DNA methylation epigenetics BCR-ABL1 |
| title | Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients |
| title_full | Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients |
| title_fullStr | Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients |
| title_full_unstemmed | Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients |
| title_short | Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients |
| title_sort | widespread aberrant alternative splicing despite molecular remission in chronic myeloid leukaemia patients |
| topic | transcriptomic complexity alternative splicing intron retention DNA methylation epigenetics BCR-ABL1 |
| url | https://www.mdpi.com/2072-6694/12/12/3738 |
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