Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia
Abstract: Epigenetic alterations have been found in chronic lymphocytic leukemia (CLL), but the functional importance of these changes remains underexplored. Here, we characterized the genome-wide histone modification landscapes of CLL using patient-derived samples across the disease course. Compare...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Blood Neoplasia |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950328024000591 |
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| author | Olivia M. Depies Qianqian Guo Yuan Gao Sutapa Sinha Zhenqing Ye Weiguo Han Kari G. Rabe Mingma S. Hoel Heather C. Darby Chuanhe Yu Esteban Braggio Sameer A. Parikh Susan L. Slager Neil E. Kay Zhiquan Wang |
| author_facet | Olivia M. Depies Qianqian Guo Yuan Gao Sutapa Sinha Zhenqing Ye Weiguo Han Kari G. Rabe Mingma S. Hoel Heather C. Darby Chuanhe Yu Esteban Braggio Sameer A. Parikh Susan L. Slager Neil E. Kay Zhiquan Wang |
| author_sort | Olivia M. Depies |
| collection | DOAJ |
| description | Abstract: Epigenetic alterations have been found in chronic lymphocytic leukemia (CLL), but the functional importance of these changes remains underexplored. Here, we characterized the genome-wide histone modification landscapes of CLL using patient-derived samples across the disease course. Compared with normal B cells, we found that the enhancers specifically lost in CLL B cells are associated with the downregulation of genes involved in immune response. Importantly, these lost enhancers exhibit an increased level of heterochromatin marks, including H3K9me3 and H3K27me3. Using the EBF1 gene locus as an example, we demonstrated that acquired H3K9me3 contributes to enhancer silencing and associated gene suppression. We further found that this aberrant chromatin signature also exists in the CLL precursor stage monoclonal B-cell lymphocytosis (MBL) cells, implicating the importance of epigenetic silencing in CLL evolution. Finally, when treated with the Bruton tyrosine kinase inhibitor ibrutinib, these silenced enhancers are relatively stable during therapy compared with the CLL-gained enhancers. In summary, we described an epigenetic silencing mechanism mediated by the heterochromatin that persists throughout CLL disease development and treatment and which may increase the risk of severe infections in MBL and CLL. |
| format | Article |
| id | doaj-art-8aaab9baf9524f82b1371e4eaf7c0775 |
| institution | Kabale University |
| issn | 2950-3280 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Neoplasia |
| spelling | doaj-art-8aaab9baf9524f82b1371e4eaf7c07752025-01-30T05:15:23ZengElsevierBlood Neoplasia2950-32802025-02-0121100059Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemiaOlivia M. Depies0Qianqian Guo1Yuan Gao2Sutapa Sinha3Zhenqing Ye4Weiguo Han5Kari G. Rabe6Mingma S. Hoel7Heather C. Darby8Chuanhe Yu9Esteban Braggio10Sameer A. Parikh11Susan L. Slager12Neil E. Kay13Zhiquan Wang14Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MNDivision of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MNDepartment of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, OHDivision of Hematology, Department of Medicine, Mayo Clinic, Rochester, MNGreehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TXDivision of Hematology, Department of Medicine, Mayo Clinic, Rochester, MNDivision of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MNDivision of Hematology, Department of Medicine, Mayo Clinic, Rochester, MNDivision of Hematology, Department of Medicine, Mayo Clinic, Rochester, MNThe Hormel Institute, University of Minnesota, Austin, MNDepartment of Hematology and Oncology, Mayo Clinic, Phoenix, AZDivision of Hematology, Department of Medicine, Mayo Clinic, Rochester, MNDivision of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN; Division of Computational Biology, Mayo Clinic, Rochester, MNDivision of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN; Department of Immunology, Mayo Clinic, Rochester, MN; Correspondence: Neil E. Kay, Mayo Clinic, 200 1st St SW, Rochester, MN 55905;Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN; Correspondence: Zhiquan Wang, Mayo Clinic, 200 1st St SW, Rochester, MN 55905;Abstract: Epigenetic alterations have been found in chronic lymphocytic leukemia (CLL), but the functional importance of these changes remains underexplored. Here, we characterized the genome-wide histone modification landscapes of CLL using patient-derived samples across the disease course. Compared with normal B cells, we found that the enhancers specifically lost in CLL B cells are associated with the downregulation of genes involved in immune response. Importantly, these lost enhancers exhibit an increased level of heterochromatin marks, including H3K9me3 and H3K27me3. Using the EBF1 gene locus as an example, we demonstrated that acquired H3K9me3 contributes to enhancer silencing and associated gene suppression. We further found that this aberrant chromatin signature also exists in the CLL precursor stage monoclonal B-cell lymphocytosis (MBL) cells, implicating the importance of epigenetic silencing in CLL evolution. Finally, when treated with the Bruton tyrosine kinase inhibitor ibrutinib, these silenced enhancers are relatively stable during therapy compared with the CLL-gained enhancers. In summary, we described an epigenetic silencing mechanism mediated by the heterochromatin that persists throughout CLL disease development and treatment and which may increase the risk of severe infections in MBL and CLL.http://www.sciencedirect.com/science/article/pii/S2950328024000591 |
| spellingShingle | Olivia M. Depies Qianqian Guo Yuan Gao Sutapa Sinha Zhenqing Ye Weiguo Han Kari G. Rabe Mingma S. Hoel Heather C. Darby Chuanhe Yu Esteban Braggio Sameer A. Parikh Susan L. Slager Neil E. Kay Zhiquan Wang Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia Blood Neoplasia |
| title | Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia |
| title_full | Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia |
| title_fullStr | Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia |
| title_full_unstemmed | Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia |
| title_short | Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia |
| title_sort | aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia |
| url | http://www.sciencedirect.com/science/article/pii/S2950328024000591 |
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