Epigenetic regulator genes direct lineage switching in <i>MLL/AF4</i> leukemia
Ricky Tirtakusuma, Katarzyna Szołtysek, Paul Milne, Vasily V. Grinev, Anetta Ptasinska, Paulynn Suyin Chin, Claus Meyer, Sirintra Nakjang, Jayne Y. Hehir‐Kwa, Daniel Williamson, Pierre Cauchy, Peter Keane, Salam A. Assi, Minoo Ashtiani, Sophie G. Kellaway, Maria Rosaria Imperato, Fotini Vogiatzi, Elizabeth K. Schweighart, Shan Lin, Mark Wunderlich, Janine Stutterheim, Alexander Komkov, Elena Zerkalenkova, Paul Evans, Hesta McNeill, Alex Elder, Natalia Martinez-Soria, Sarah Fordham, Yuzhe Shi, Lisa J. Russell, Deepali Pal, Alexandra Smith, Zoya Kingsbury, Jennifer Becq, Cornelia Eckert, Oskar A. Haas, Peter Carey, Simon Bailey, Roderick Skinner, Natalia Miakova, Matthew Collin, Venetia Bigley, Muzlifah Haniffa, Rolf Marschalek, Christine J. Harrison, Catherine Cargo, Denis M. Schewe, Yulia Olshanskaya, Michael J. Thirman, Peter N. Cockerill, James C. Mulloy, Helen J. Blair, Josef Vormoor, James M. Allan, Constanze Bonifer, Olaf Heidenreich, Simon Bomken
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.