B-cell acute lymphoblastic leukaemia (B-ALL) is one of the most common forms of childhood cancer. The overall survival rate is more than 80%, but not in all subtypes; in leukaemia with the highest incidence among infants, in particular, it does not reach 40%.
For this specific subtype, with a poor prognosis, researchers from the Josep Carreras Leukaemia Research Institute and the National Cancer Research Centre (CNIO) have achieved the first cell model that simulates the disease in patients.
The new model reproduces what happens in the cells of children, often newborns. It is an essential tool in research to develop new therapeutic strategies and has therefore been published in Blood, a leading scientific journal in haematology.
Gene editing to fuse genes
The subtype of B-cell acute lymphoblastic leukaemia that the model recreates is specifically the one that carries the fusion between the MLL and AF4 genes. Independent gene fusions are a common type of alteration in cancer; when they occur, they have the ability to produce fusion proteins, sometimes with new and unexpected functions.
MLL::AF4 fusion in childhood B-cell acute lymphoblastic leukaemia occurs during foetal development, and involves DNA exchange between chromosomes 4 and 11. The resulting protein can activate cellular mechanisms that lead to leukaemia in what can be a very short space of time.
The new model has been created by means of gene editing, using the CRISPR-Cas9 tool. Both foetal and neonatal cells have been edited, provided by the Barcelona Blood and Tissue Bank and the MRC/Wellcome Trust Centre (United Kingdom).
The model reproduces different subtypes
There are several subtypes of MLL::AF4 fusion B-ALL, in which the merged fragments change. The new model reliably reflects the differences between the subtype of B-ALL leukaemia in children under one year of age, and that of older children, which represents a significant advance.
The results also show that the differences between subtypes of childhood ALL-B with MLL::AF4 fusion are related to the DNA fragments involved in gene fusion, and not so much with the time the alteration occurs, and they provide the scientific community with a new cellular model of the disease which is robust and closer to what happens in patients.
The study is directed by Pablo Menéndez, of the Josep Carreras Institute, and the lead authors are Clara Bueno, of the Josep Carreras Institute; and Raúl Torres-Ruiz, of the National Cancer Research Centre (CNIO).
Image: Raúl Torres-Ruiz, one of the lead authors, at his CNIO lab. / Laura M. Lombardía / CNIO.
Reference article: Clara Bueno, Raul Torres-Ruíz, Talia Velasco-Hernandez, Oscar Molina, Paolo Petazzi, Alba Martinez-Moreno, Virginia Carolina Rodríguez-Cortez, Meritxell Vinyoles, Sandra Cantilena, Owen Williams, Nerea Vega-García, Sandra Rodriguez-Perales, José Carlos Segovia, Oscar Quintana-Bustamante, Anindita Roy, Claus Meyer, Rolf Marschalek, Alastair Smith, Thomas A. Milne, Mario F. Fraga, Juan Ramón Ramón Tejedor, Pablo Menendez; “A human genome editing-based MLL::AF4 B-cell ALL model recapitulates key cellular and molecular leukemogenic features”. Blood 2023; blood.2023020858.