The pathobiology of pediatric B-cell precursor acute lymphoblastic leukemia
De pathobiologie van voorloper B-cel acute lymfatische leukemie bij kinderen
Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease, caused by the malignant transformation of either T-cell (~15% of the cases) or B-cell progenitors (~85% of the cases). To further improve the survival of children with ALL, new targeted treatment strategies are warranted. Therefore, it is essential to gain insight in the pathobiology of childhood ALL.
The scope of this thesis is on pediatric B-cell precursor ALL (BCP-ALL). We studied:
1) the occurrence of tyrosine kinase fusion genes (i.e. ABL and JAK class) and JAK2 mutations in pediatric BCP-ALL cases;
2) the efficacy of JAK inhibitors in JAK2 aberrant (translocations and point mutations) leukemic cells;
3) the potential of STAP1 as therapeutic target for DUX4-rearranged ALL cases;
4) the association between copy number aberrations in B-cell development genes (e.g. IKZF1, PAX5), long‑term prognosis, and cellular drug resistance;
5) the supportive properties and gene expression profiles of mesenchymal stromal cells derived from pediatric BCP-ALL patients and healthy pediatric donors.
Our results show efficacy of new precision medicines, i.e. JAK inhibitors, but we also identified important limitations that should be overcome. Moreover, we show that the genetic context matters and that the effect of anti-cancer drugs should be studied in the proper genetic context. Lastly, we show that mesenchymal stromal cells are not actively involved in BCP-ALL leukemogenesis. Instead leukemic cells actively modulate signaling pathways in MSCs to support BCP-ALL cell survival. Targeting this interaction between BCP‑ALL cells and MSCs might be an attractive alternative treatment strategy.
|Keywords||Pediatric, B-cell precursor acute lymphoblastic leukemia, bone marrow micro-environment, drug resistance, JAK2, mesenchymal stromal cells, BCR-ABL1-like leukemia, IKZF1, targeted therapy, precision medicines, tyrosine kinase fusion genes|
|Promotor||M.L. den Boer (Monique) , R. Pieters (Rob)|
|Publisher||Erasmus University Rotterdam|
|Note||For copyright reasons there is a partial embargo for this dissertation|
Steeghs, E.M.P. (2018, July 4). The pathobiology of pediatric B-cell precursor acute lymphoblastic leukemia. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/105998