Tirtakusuma, Ricky, Szoltysek, Katarzyna, Milne, Paul, Grinev, Vasily, Ptasinska, Anetta, Chin, Paulynn Suyin, Meyer, Claus, Nakjang, Sirintra, Hehir-Kwa, Jayne Y., Williamson, Daniel, Cauchy, Pierre, Keane, Peter, Assi, Salam a, Ashtiani, Minoo, Kellaway, Sophie G., Imperato, Maria R., Vogiatzi, Fotini, Schweighart-James, Elizabeth K., Lin, Shan, Wunderlich, Mark, Stutterheim, Janine, Komkov, Alexander, Zerkalenkova, Elena, Evans, Paul, McNeill, Hesta Varey, Elder, Alex, Martínez-Soria, Natalia, Fordham, Sarah E., Shi, Yuzhe, Russell, Lisa J., Pal, Deepali, Smith, Alexandra G., Kingsbury, Zoya, Becq, Jennifer, Eckert, Cornelia, Haas, Oskar A,, Carey, Peter, Bailey, Simon, Skinner, Roderick, Miakova, Natalia, Collin, Matthew, Bigley, Venetia, Haniffa, Muzlifah, Marschalek, Rolf, Harrison, Christine J., Cargo, Catherine A., Schewe, Denis Martin, Olshanskaya, Yulia, Thirman, Michael J., Cockerill, Peter N., Mulloy, James C., Blair, Helen J., Vormoor, H. Josef, Allan, James M., Bonifer, Constanze, Heidenreich, Olaf and Bomken, Simon (2022) Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia. Blood, 140 (17). pp. 1875-1890. ISSN 0006-4971
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Abstract
The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.
| Item Type: | Article |
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| Additional Information: | Funding information: This study was supported by a Cancer Research UK Centre Studentship (C27826/A17312) and Newcastle University Overseas Research Scholarship (R.T.); a CRUK program grant (J.V., O.H.) (C27943/A12788); a Kika programme grant (329) (O.H., J.V.); grants from the North of England Children’s Cancer Research Fund (O.H., J.V., S.B.); Bloodwise grants 12055 and 15005 (O.H.); and a grant from the Kay Kendall Leukaemia Fund (KKL1142) (O.H.). S.B. was supported by an NIHR Academic Clinical Lectureship (CL-2012-01-002), the Sir Bobby Robson Foundation Clinical Fellowship, and a Medical Research Council Clinician Scientist Fellowship (MR/S021590/1). Work in C.B./P.N.C.’s laboratory was funded by a programme grant from Bloodwise (15001). Work in J.M.A.’s laboratory was funded by a programme grant from Bloodwise (13044). E.Z. was supported by a Russian Foundation for Basic Research (RFBR) grant (17-29-06052). Research in the V.V.G. laboratory was supported in part by the Ministry of Education of the Republic of Belarus, grant 3.04.3. Research in A.K.’s laboratory was supported by an Russell Sage Foundation (RSF) grant (20-75-10091). The study made use of data generated by the St Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, phs000218, managed by the National Cancer Institute (supplemental Methods). |
| Uncontrolled Keywords: | MLL/AF4, KMT2A/AFF1, acute lymphoblastic leukaemia, nucleosome 52 remodelling and deactylation complex (NuRD), chromatin remodelling |
| Subjects: | A300 Clinical Medicine C100 Biology |
| Department: | Faculties > Health and Life Sciences > Applied Sciences |
| Related URLs: | |
| Depositing User: | Rachel Branson |
| Date Deposited: | 17 Aug 2022 13:31 |
| Last Modified: | 30 Nov 2022 13:00 |
| URI: | https://nrl.northumbria.ac.uk/id/eprint/49886 |
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