A European research project has examined the genetic causes of glucocorticoid resistance in infants treated for B-cell acute lymphoblastic leukaemia (B-ALL). The findings open up new opportunities to improve the survival rates for these hard-to-treat cancers.
B-ALL is the most common paediatric cancer, with an overall five-year survival rate of 85% or more. This is thanks to well-established treatment regimens including glucocorticoids. However, for some infants (less than one year of age) with B-ALL, their disease is resistant to glucocorticoids, and survival rates as a result are less than 30%.
Most of these glucocorticoid-resistant cancers carry rearrangements in the MLL gene (also known as KMT2A), in particular the fusion between MLL and AF4. The team set out to investigate the causes of the resistance to glucocorticoids in these cancers, using samples of cancer cells donated by patients, human cell lines, and mouse models.
Reporting in Blood, they found the MLL-AF4 fusion protein activates the production of the protein NG2. This deactivates the glucocorticoid receptor – via other proteins called FLT3 and AP-1 – making cancer cells insensitive to standard treatment.
Researchers led by Dr Belén López-Millán and Dr Clara Buenoat, of the Josep Carreras Leukaemia Research Institute, worked with other teams in Spain, Italy, Germany, the Netherlands and the University of Oxford, UK, on the research.
The scientists say the findings should be a “goldmine” for clinical research because they open up new targets to re-sensitise infant B-ALL to glucocorticoids and improve the care for patients.
They state: “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.”
Source:
Lopez-Millan B, Rubio-Gayarre A, Vinyoles M, Trincado JL, Fraga MF, Fernandez-Fuentes N, Guerrero-Murillo M, Martinez-Moreno A, Velasco-Hernandez T, Falgàs A, Panisello C, Valcarcel G, Sardina JL, López-Martí P, Javierre BM, Del Valle-Pérez B, García de Herreros A, Locatelli F, Pieters R, Bardini M, Cazzaniga G, Rodríguez-Manzaneque JC, Hanewald T, Marschalek R, Milne TA, Stam RW, Tejedor JRR, Menendez P, Bueno C. (2024) “NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLL-r B-ALL by regulating NR3C1 expression.” Blood, 2 August 2024, doi: 10.1182/blood.2023022050.
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