Resolving the prenatal events in pediatric leukemia development

In this proposal the events that precede the development of Acute Lymphoblastic Leukemia (ALL) will be explored.ALL is one of the most common cancers in children and despite advances in treatment some sub-groups still suffer poor prognosis.

The initiating mutations are known to occur during fetal life, and insight into these prenatal molecular and cellular events are key to improve treatment strategies in the future.The initiation of disease will be studied in a murine model expressing the MLL-AF4 oncogene, known to cause an aggressive B-ALL with poor prognosis.

The prenatal origin and molecular signature of the pre-leukemic clone will be investigated in the embryo.

From the molecular signature, candidate target genes will be assessed and evaluated with the aim to explore new therapeutic approaches.

Furthermore, human primary ALL samples will be used to identify and characterize pre-leukemic and leukemia initiating cells in established disease.

The blast population will be sub-fractionated, and the molecular signature investigated at the single cell level, with the aim to identify the molecular identity of leukemia initiating cells.Knowledge of the early disease initiating steps can reveal novel therapeutic approaches and may even be used to develop preventive strategies in the future.

Leukemia initiating cells can respond poorly to treatment and contribute to relapse, highlighting the need to specifically identify and target these cells.