14 February 2022

Researchers have identified a potential new method of preventing acute lymphoblastic leukaemia (ALL) among children with a genetic predisposition to the disease.

One in twenty cases of B-cell ALL are triggered by an underlying genetic predisposition. One such predisposition is when children carry one altered and one normal copy of the PAX5 gene. This gene codes for a protein necessary for B-lymphocytes in the immune system.

Researchers at St. Jude Children’s Research Hospital, Memphis, USA, and the University of Salamanca in Spain previously discovered, in tests on mice, that B-cell ALL develops in a small percentage of mice that carry one altered copy of the Pax5 gene (called Pax5+/- mice). However, this only occurs if the immune system is activated by a pathogen or other stressor, they say.

In these earlier tests, the team also discovered that immature B-lymphocytes in these mice are particularly dependent on the cytokine interleukin-7. They showed that blocking its signalling – using the drug ruxolitinib – led to increased cell death in the lab.

This new study, published in Cancer Research, shows that ruxolitinib given to the Pax5+/- mice in early life reduces the risk of B-cell ALL developing. Following exposure to infection, only one in 29 mice given ruxolitinib developed the disease (3.4%), compared with eight in 34 (23.5%) of untreated mice.

“These findings provide the first in vivo evidence for a potential strategy to prevent B-cell acute lymphoblastic leukaemia development,” the authors conclude.

Dr Kim Nichols from St Jude, one of the lead authors of the study, said: “I realise these are early days, but I cannot help getting excited about the findings. This is the first kernel of hope for a medical intervention to prevent hereditary forms of leukaemia or other hereditary cancers in general.”

Source: Casado-García A, Isidro-Hernández M, Oak N, Mayado A, Mann-Ran C, Raboso-Gallego J, Alemán-Arteaga S, Buhles A, Sterker D, Sánchez EG, Martínez-Cano J, Blanco O, Orfao A, Alonso-López D, De Las Rivas J, Riesco S, Prieto-Matos P, González-Murillo Á, Garcia Criado FJJ, Garcia Cenador MB, Radimerski T, Ramírez-Orellana M, Cobaleda C, Yang JJ, Vicente-Dueñas C, Weiss A, Nichols KE, Sánchez-García I. (2022) “Transient inhibition of the JAK/STAT pathway prevents B-ALL development in genetically predisposed mice.” Cancer Research, doi: 10.1158/0008-5472.CAN-21-3386

Link: https://cancerres.aacrjournals.org/content/early/2022/02/03/0008-5472.CAN-21-3386

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