SUMMARY
MLL Leukemia is one of the worst children’s cancers. Its early appearance, in the baby’s first year, and poor prognosis underline the importance of looking for biomarkers that may help to stratify cancer into different risk categories, and that could provide a target to be addressed with a drug for treatment. The changes in the MLL gene that give a name to the disease can include alterations in different pathways in the cell, which have to be studied.
PROJECT OVERVIEW
Acute leukaemia is the most frequent cancer in children. Recently, the development of new technologies has significantly increased the knowledge of the biology of leukaemia. New biomarkers and prognostic factors have been discovered, which have led to a better stratification of patients and to the application of treatments adapted to the specific risk of each case. Although there has been a remarkable improvement in the survival rate of children with acute leukaemia in the past few years, some patients still have a poor outcome and die of the disease. There is, therefore, a need to find new biomarkers to guide these high-risk patients’ treatment or, even better, to be used as therapeutic targets.
Acute leukaemias with alterations in the MLL gene (mixed lineage leukaemia) represent a heterogeneous subgroup of patients. These leukaemias can occur at any age, soon after birth, or during childhood, adulthood or old age. The appearance of this leukaemia may vary but, in general, the presence of MLL alterations confers a poor prognosis, which is even worse in neonatal leukaemia. Infant or neonatal leukaemia (diagnosed in children under 1 year of age) is a special subgroup, characterised by frequent MLL gene anomalies and a devastating prognosis.
The objective of our project is to try to understand the role in the onset of MLL leukaemias of certain molecular pathways (called Wnt/beta-catenin, Notch1, FLT3 and HOX), which are very important in embryogenesis and the forming of blood cells. This is important to allow us to:
- Understand why some MLL leukaemias occur very aggressively in newborns, while other cases have much longer latency and will appear in childhood or in adults.
- Identify therapeutic targets. The more we know about the leukaemia cell and the pathways involved, the better we will be able to treat patients with specific treatments.
Since MLL gene alterations can occur at any age, the findings of our project would not only help paediatric patients, but also adult patients with leukaemia and MLL alterations. On the other hand, one of the specific objectives of the project is to offer a technique for the diagnosis of any MLL alteration. This will allow identifying rare alterations and cases with complex gene anomalies, which are very frequent in paediatric acute leukaemia.
In short, this project hopes to improve the diagnosis of MLL leukaemias and understand the role of the molecular pathways involved in the formation of blood cells and embryogenesis in the development of leukaemia, in order to find specific treatments for these patients.
RESULTS
In 2014 we analysed a group of 227 children with leukaemia, between the ages of 0 and 18 years, including 33 with changes in the MLL gene and we observed that in these cases, the alteration of a second gene pathway was also present, that of FLT3. This change was more common in infants, and there was a relationship between the protein produced by this FL3 gene and the response to some chemotherapy treatments. We also know that this alteration of FLT3 indicates a poor prognosis. However, it is not all bad news, since there are some treatments in the clinical trial phase targeted to cancel the action of this alteration to the FLT3 gene.
In 2015, we expect to complete the analysis of the data, with the aim of finding a pattern that occurs in all these pathways and allows us to distinguish between patients with better or worse prognosis. In particular, we will focus on comparative analysis of infants and older patients and, in a second analysis, we will compare patients with and without the MLL alteration, independent of age, for the purpose of offering tailored treatments that are risk-adjusted for each case.