Leukaemia, or blood cancer, has several subtypes. One is chronic myeloid leukaemia (CML), which affects the bone marrow and leads to an overproduction of white blood cells. The treatment of choice is imatinib, a tyrosine kinase inhibitor, but therapy response varies greatly among CML patients because some of them develop resistance quickly.   

Little is known about the relationship genetic variation and response to therapy, but Mengge Yu, Giselle Sek Suan Nah and colleagues from Duke-NUS Medical School in Singapore now offer an explanation in the journal Leukemia for a subset of CML patients. It centres on a genetic variation (polymorphism) in the gene encoding the protein BIM: BCL-2 interacting death mediator. BIM is involved in the regulation of cell death and thus plays a crucial role in the removal of damaged or unwanted cells. Many cancer therapies activate BIM to boost the elimination of tumour cells.   

The Duke-NUS team has now succeeded in creating a humanised CML mouse model that also contains the genetic BIM variations. In these mice, they found that BIM no longer contributes to the killing of tumour cells, but instead protects them. As a result, the tumour cells survive longer and can continue to grow and spread.  

At the same time, it became clear that tumour cells with the BIM variant rely heavily on the protein MCL-1 for their survival. A combination therapy of imatinib and an MCL-1 blocker effectively targeted the tumour cells in cell studies.  

According to the Duke-NUS team, this shows that genetic profiling is essential for selecting the right treatment option as early as possible. For example, the BIM polymorphisms studied here are relatively common in East Asian populations, including Chinese, Japanese and Koreans. In these groups, 12-15% carry a BIM variant, which puts them at greater risk of developing resistance to imatinib, leading to more aggressive cancer cell growth and a worse prognosis.   

Taking this into account at the outset can save valuable time in the treatment process. And this is not only true for CML, the researchers say. Some types of lung cancer are also treated by activating BIM, and perhaps the same mechanisms are involved in the development of resistance. This could create new options for developing precision therapy for other patient groups.   

Mengge Yu, Giselle Sek Suan Nah, et al., The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies, Leukemia (2024), doi:10.1038/s41375-024-02418-0