How chameleon cancers can change their spots to survive treatment
A new study has shown that some leukaemias can evade treatment by altering their appearance and identity by changing the way that their genomes make cell fate decisions.
A team of researchers from Birmingham, Newcastle and the Netherlands investigated the responses of children undergoing therapy for B-cell acute lymphoblastic leukemia (ALL). In children ALL is often caused by rearrangements in the MLL gene which result in the production of abnormal MLL fusion genes such as MLL-AF4. MLL is a chromatin modifier that plays an essential role in regulating gene expression during early development and hematopoiesis by methylating histones in regions of active chromatin. The MLL gene is defined as “Mixed Lineage Leukaemia” because it was originally identified in cases of leukaemia where a mixture of both lymphoid and myeloid cells were present.
Current ALL therapies include immunotherapies directed against B cell-specific proteins expressed on the surface of ALL cells. However, children being treated for B-ALL sometimes relapse not with ALL but with Acute Myeloid Leukaemia (AML) which express myeloid and not B cell-specific proteins, thereby evading specific immunotherapy against targets such as CD19.
This new study investigated the molecular basis of lineage switching and found that it is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes from the lymphoid to the myeloid lineage. These changes included loss of function of the chromatin modifier CHD4 and the repressive NuRD complex, and this loss was found to be sufficient to initiate activation of the myeloid transcriptional programme. This mechanism of leukaemia evolution is summarised in the following model.
This research was just announced in a Press Release describing the recent publication in the Journal Blood: Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia Ricky Tirtakusuma, .........., Peter N. Cockerill, James C. Mulloy, Helen J. Blair, Josef Vormoor, James M. Allan, Constanze Bonifer, Olaf Heidenreich, Simon Bomken Blood (2022) 140 (17): 1875–1890. doi.org/10.1182/blood.2021015036
The research article was also accompanied by a commentary in Blood written by Ilaria Iacobucci and Charles Mullighan: KMT2A-rearranged leukemia: the shapeshifter