Scientists have made further discoveries about the role of the metabolism in mechanism of leukaemia development.
B cells in the immune system undergo multiple rounds of genetic editing as they develop antibodies. While they are doing this, they are vulnerable to mutations which could lead to them becoming cancerous and developing into B-cell acute lymphoblastic leukaemia (B-ALL). However, they are normally prevented from doing so by proteins which limit the amount of glucose that can enter the cell, such as IKZF1 and PAX5, so-called “metabolic gatekeepers”. This limits the fuel available for leukaemia cells to develop.
Now a team led by Dr Markus Müschen of Yale Cancer Center, Connecticut, USA, have discovered that a molecule called PON2 can bypass these metabolic gatekeepers. They found high levels of PON2 in B-ALL cell samples, and that high PON2 levels correlated with reduced survival in paediatric and adult B-ALL in clinical trials.
Further tests indicate that raised levels of PON2 increase the chance of B cells becoming leukaemic due to greater energy production in the cell. PON2 enables glucose-uptake activity of a glucose transporter by releasing it from its usual inhibitor protein.
The team also found that drugs which exploited the dependence of B-ALL cells on PON2 could improve survival in mouse models of the disease.
Dr Müschen and colleagues believe their discoveries about the role of metabolic gatekeepers in leukaemia could aid the development of new treatments. Their findings were published online last week in the Proceedings of the National Academy of Sciences.
Dr Müschen says: “PON2 was critical for glucose uptake and energy production and loss of PON2 prevented leukaemia development.
“High levels of PON2 did not only predict poor outcomes of leukaemia patients in clinical trials, but it also contributes to a more aggressive course of disease.”
He adds: “From a treatment perspective, the study suggests that the enzyme activity of PON2 can be leveraged to selectively kill B-cell acute lymphoblastic leukaemia cells. Targeting of PON2 could be developed as a novel therapeutic intervention strategy to overcome drug resistance.”
Pan L, Hong C, Chan LN, Xiao G, Malvi P, Robinson ME, Geng H, Reddy ST, Lee J, Khairnar V, Cosgun KN, Xu L, Kume K, Sadras T, Wang S, Wajapeyee N, Müschen M. “PON2 disrupts B cell metabolic gatekeeper function and promotes leukemia induction.” PNAS, doi: 10.1073/pnas.2016553118
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