Scientists have created a model of a complicated subtype of childhood acute lymphoblastic leukaemia (ALL) using gene-editing techniques.
Spanish researchers say the model replicates a particularly complicated subtype of childhood acute lymphoblastic leukaemia, B-cell leukaemias with MLL::AF4 fusions.
Researchers of the Josep Carreras Leukaemia Research Institute and the Spanish National Cancer Research Centre (CNIO) say the new model shows a disease progression very similar to that seen in children and babies.
B-cell acute lymphoblastic leukaemia (B-ALL) is one of the most common paediatric cancers, and while survival rates are above 80%, some of B-ALL subtypes have a poor prognosis.
B-ALL that harbours the fusion between the MLL and AF4 genes (also known as KMT2A and AFF1, respectively) has a survival rate of less than 40%. To date, there has not been a reliable model that would allow researchers to thoroughly study this subtype, the Spanish team says.
A team led by Dr Pablo Menéndez, of the Josep Carreras Leukaemia Research Institute, has created the model by genetically editing both foetal and neonatal human blood stem cells, provided by the Barcelona Blood and Tissue Bank and the MRC/Wellcome Trust Centre (UK).
The study, led by Dr Clara Bueno, of the Josep Carreras Institute, and Dr Raúl Torres-Ruiz, of the Spanish National Cancer Research Center (CNIO), is published in Blood.
The research results demonstrate that the differences between the subtypes of childhood B-ALL with MLL::AF4 fusion are related more to the DNA fragments involved in the gene fusion, and not so much to the time the alteration appears.
In infants under one year old, this subtype usually involves a fusions from intron 11 or 12 of the MLL gene. In children over the age of one, the fusion most often occurs from intron 10 of MLL. The model the Spanish team has created reflects these differences, which they say is a major advance for modelling this subtype.
The team says the new tool will be essential to help scientists better understand childhood MLL::AF4 B-LLA.
The researchers say: “The study also provides the scientific community with a new, robust of the disease, closer to what happens in patients. This tool will be essential in the coming years to better understand childhood MLL::AF4 B-LLA and to develop specific therapeutic strategies to improve its survival rate.”
Bueno C, Torres-Ruíz R, Velasco-Hernandez T, Molina O, Petazzi P, Martinez-Moreno A, Rodríguez-Cortez VC, Vinyoles M, Cantilena S, Williams O, Vega-García N, Rodriguez-Perales S, Segovia JC, Quintana-Bustamante O, Roy A, Meyer C, Marschalek R, Smith A, Milne TA, Fraga MF, Tejedor JRR, Menendez P. (2023) “A human genome editing-based MLL::AF4 B-cell ALL model recapitulates key cellular and molecular leukemogenic features.” Blood, doi: 10.1182/blood.2023020858
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