How does neutropenia increase the risk of AML and MDS?

Severe congenital neutropenia increases the risk of myelodysplastic syndrome and acute myeloid leukaemia. What do we know today about the haematological processes that lead to leukaemogenesis?

Interview with Prof Julia Skokowa

Leukaemogenesis in patients with congenital mutations

People with congenital mutations in certain genes are already susceptible to bacterial infections as infants. Although neutropenia can be treated with growth factors (cytokines), about 20% of them develop MDS or AML.

The deregulated expression of transcription factors, cytokine receptors and effector molecules leads to the blockade and excessive proliferation of haematopoietic stem cells, and thus to leukaemogenesis. A better understanding of these processes can lead to targeted therapies that minimise the risk and improve the course of these diseases.

Role of senescence in leukaemia and pre-leukaemic symptoms

For Prof Skokowa, the term senescence is not entirely appropriate for chronic neutropenia. She therefore uses the term "quiescence". This is because the cells are only in a resting state and are not completely inactive. Genetic mutations or other mutations that play a role in the context of leukaemogenesis can awaken these cells, causing them to proliferate excessively and ultimately become leukaemogenic.

What influence does age have on leukaemogenesis?

It has recently been found that specific mutations occur in patients with increasing age and that these mutations can lead to the clonal expansion of certain blood cells, which is known as clonal haematopoiesis. In this process, a certain haematopoietic stem cell proliferates more dominantly than others. The mutations that lead to clonal haematopoiesis play an important role in the epigenetic regulatory mechanisms of all these processes.

Haematopoiesis and leukaemogenesis: risk of relapse in haematological malignancies?

Although leukaemia cells appear uniform under the microscope, they exhibit heterogeneity. There are leukaemia stem cells, quiescent cells and already proliferating cells, some of which have specific new gene mutations or chromosomal translocations. The therapy response of patients depends on this heterogeneity and determines whether a relapse occurs or not.

Factors and strategies for overcoming therapy resistance

Increasingly, factors leading to resistant leukaemias are being identified. In the group of patients studied, it was recently discovered that certain proteins are highly expressed in the leukaemia cells and are associated with resistance to therapy. A significant proportion of leukaemia stem cells, senescents or quiescents contribute to the development of therapy resistance.