B-ALL is the most common pediatric cancer and, over the years and thanks to a very effective treatment based on glucocorticoids, its 5-year survival rates have reached 85% and beyond. However, there is a B-ALL subtype, commonly found in infants (less than 1 year old), that responds very poorly to glucocorticoids and, with no other therapeutic alternative, its prognosis is dismal and survival rates still fall below 30%. The common feature of this glucocorticoid-resistant B-ALL subtype is the rearrangement of the MLL gene.
This means that a DNA fragment with this gene has moved elsewhere in the genome, in a sort of random genetic cut-and-paste. This is actually very common in and, depending on where the fragment is pasted, there might be consequences. In most cases of B-ALL with MLL rearrangements (MLLr B-ALL), this gene fuses with another one named AF4, producing a new fusion protein (MLL-AF4) with unexpected activities.
A complex series of events The findings of the team, spearheaded by Dr. Belén López-Millán (also member of the University of Granada) and Dr. Clara Bueno, in collaboration with Dr.
Jose Luis Sardina and Dr. Biola Javierre (Josep Carreras Institute) and Dr. Juan Ramón Tejedor and Mario Fraga's team (CINN/CSIC—ISPA—IUOPA), as well as other research teams from Spain, Italy, Germany and the UK, show how the events following the MLL-AF4 fusion end up producing the characteristic glucocorticoid resistance in MLLr B-ALL and the dismal prognosis of the disease.
The research has recently been in the . Using state-of-the-art genomic and proteomic methodologies, the team discovered that the MLL-AF4 fusion protein stimulates the production of NG2, a protein not found in healthy hematopoietic cells. The consequence of this aberrant production of NG2 is that it interacts with a sensor the cell uses to respond to growth signals during development, a protein called FLT3, and activates it even in the absence of its specific proliferation signals.
The activation of FLT3 promotes the proliferation mechanisms of the cell, a hallmark of cancer, one of which is the inactivation of the glucocorticoid receptor, rendering the cell insensitive to the for B-ALL. The final effector of this inactivation is the well-known repressor protein AP-1. Despite the fact that researchers used basically in vitro and ex vivo methodologies (mice xenografts), and their results are still in the preclinical stage, all these findings are a goldmine to clinical research, because the more cellular systems involved, the more targets to attack with carefully designed drugs or immunotherapies in the future.
With this new knowledge, an alternative treatment for infants with glucocorticoid-resistant MLLr B-ALL seems a bit closer, and so is hope for many families. Belén Lopez-Millan et al, NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLL-r B-ALL by regulating NR3C1 expression, (2024)..
