Why do some patients respond well to treatment while others do not, even when they appear to have the same type of cancer?

This is one of the key questions behind the 7RMADs research project, led by João Barata, which has just been awarded €500,000 in funding by the “la Caixa” Foundation. Focusing on acute lymphoblastic leukemia (ALL), the most common childhood cancer, the team aims to understand whether the timing of the first cancer-causing mutation can influence how the disease develops and responds to treatment.

ALL originates in immature immune cells, most commonly B-cell precursors – a type of cell involved in the body’s defenses. Although current treatments are highly effective in children, outcomes remain less favorable in adults, and therapies can cause significant short- and long-term side effects. Relapses and treatment-resistant cases are particularly difficult to manage, highlighting the need for more personalized approaches.

At the heart of the project is a molecule essential for the normal development of immune cells: the interleukin-7 receptor (IL-7R). João Barata’s team had previously shown that mutations in IL-7R can act as an initiating event in leukemia development.

The new project takes this research a step further. Rather than focusing solely on the mutation itself, the researchers want to understand whether the stage of cellular development at which the mutation first occurs influences the characteristics of the resulting disease.

Blood cells develop through a hierarchical process. Hematopoietic stem cells gradually give rise to increasingly specialized progenitor cells, which eventually generate different types of blood and immune cells. A mutation may arise early in this process, when cells retain a broad capacity to differentiate, or later, when they are already committed to a specific cellular fate.

“Our data suggest that the same oncogenic mutation can produce leukemias that look very similar under the microscope but behave quite differently, depending on the stage of cellular development at which the first mutation occurred. The timing of a mutation may be just as important as the mutation itself,” explains João Barata.

Using sophisticated animal models, the team observed that activating the same IL7R mutation at different stages of blood cell development consistently leads to B-cell acute lymphoblastic leukemia. However, despite sharing the same diagnosis and apparently identical diseased cells, these leukemias display distinct gene expression profiles and biological properties.

The findings suggest that leukemia cells may retain a kind of “cellular memory” of the developmental stage at which the first cancer-causing event occurred. Even as they continue to differentiate and become malignant, they appear to preserve traces of their early history.

This biological memory could have important clinical implications. Leukemias originating at earlier stages of development may be more resistant to chemotherapy. The researchers have also identified transcription factors that could help refine diagnosis.

“If these findings are confirmed, these molecular signatures could help identify patients who are less likely to respond to conventional therapies and who might benefit from alternative treatment strategies,” says João Barata.

The project will investigate the mechanisms underlying this biological memory, characterize the full range of differences between leukemias originating in different cell types, and explore whether these differences can be exploited therapeutically.

The implications could extend far beyond leukemia. The researchers believe the same principle may apply to other oncogenes and potentially to other types of cancer. If so, this work could challenge the traditional view that cancers are defined primarily by the mutations they carry, highlighting the importance of understanding when and where those mutations first arise.

Ultimately, the project seeks to answer a fundamental question: can a cell’s history leave a lasting mark on cancer? By revealing how the timing of a mutation influences disease behavior, João Barata and his team hope to open up new possibilities for prognosis, patient stratification and the development of more effective treatments for leukemia and potentially other cancers.