‘Chameleon cancers’ change colors to evade treatment, study reveals

UTRECHT, Netherlands — Cancer, in general, is notoriously hard to treat. Now, new research is exposing the chameleon-like tactics certain types of cancer employ to evade treatments. Scientists from the Princess Máxima Center for Pediatric Oncology have discovered that some leukemias are capable of altering their appearance and identity by changing the expression of their DNA.

“Our new research will help us in the future to pick out those children with leukemia who are at greatest risk of their cancer coming back, so we can adjust and personalize their treatment,” says study co-leader Professor Olaf Heidenreich, PhD, research group leader at the Princess Máxima Center for pediatric oncology, in a media release.

The team conducted this research in the Netherlands, where roughly 110 children per year develop blood cancer B-cell acute lymphoblastic leukemia (ALL). Meanwhile, in the United States, the American Cancer Society estimates that there were about 6,660 new cases of ALL in 2022. Thanks to major improvements and advancements in treatment techniques over the past 50 years, however, study authors say nine in every 10 pediatric cases are now curable.

If a patient’s leukemia does not respond to treatment, there are also promising yet not perfected immunotherapies, like antibody and immune cell-based treatments, such as CAR T-cells. However, certain blood cancers evade immune therapies by stopping the production of the cell surface proteins targeted by these therapies. Other leukemias become an entirely different type of blood cancer that these treatments aren’t capable of working against. Specifically, children with blood cancer displaying a change in the MLL gene are at an especially higher risk of their cancer returning post-treatment.

So, the research team from the Princess Máxima Center worked together with Newcastle University and the University of Birmingham to uncover one of the key mechanisms driving how these “chameleon cancers” change their appearance and identity.

How does blood cancer affect a child’s gene ‘switches’?

Study authors analyzed the tumor DNA of 12 children and adults diagnosed with ALL. Importantly, each participants’ leukemia displayed a particular change in their MLL gene. Researchers note that there were also changes in numerous on-off switches, subsequently altering the read-out of the DNA and enabling the leukemia cells to evade treatment efforts.

“When ALL cells switch their identity, the leukemia becomes extremely difficult to treat. The fact that we now understand what the drivers of this switch are has important implications for our understanding of disease development but also the response of a child to therapy. This may enable us to identify the children who are at greatest risk of relapse and gives us the opportunity to adjust and personalize their treatment,” Prof. Heidenreich adds.

“ALL cells carrying this chromosomal rearrangement have long been known to be able to relapse as a different type of blood cancer, acute myeloid leukemia (AML). By studying these switched MLL/AF4 leukemias we showed that the switch can happen in blood cells throughout different stages of development in the bone marrow. Importantly, the switch can be a result of additional genetic changes that can be caused by chemotherapy itself. As a consequence, some leukemias completely ‘re-programme’ themselves and switch identity from one cell type to another,” explains co-lead study author Dr. Simon Bomken, MRC Clinician Scientist and Honorary Consultant at Newcastle University.

“Our findings from leukemia patients that have seen this rare switching occur are encouraging. As research progresses it may be possible to find treatments that will prevent this type of switching, and the process will also help further studies to identify where other cancers show similar behavior,” adds Professor Constanze Bonifer, Chair of Experimental Haematology at the University of Birmingham’s Institute of Cancer and Genomic Sciences.

“Our study on cancer cell identity switching behavior is a good example of how important international collaboration and persistence is in scientific research. Childhood cancer is a rare disease and this specific form is even rarer it is of great importance to collect and combine data from different locations,” Prof. Heidenreich concludes.

The study appears in the journal Blood.

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