Photo from Business Wire
A pair of transcription factors protect B cells from malignant transformation by keeping the cells’ glucose and energy levels low, according to research published in Nature.
“While transformation to cancer and childhood leukemia takes large amounts of energy, we discovered that low energy levels in B cells protects from malignant transformation toward leukemia and cancer,” said study author Markus Müschen, MD, PhD, of City of Hope Comprehensive Cancer Center in Duarte, California.
“The low energy levels in normal B cells are simply too low to allow transformation to leukemia.”
Dr Müschen and his colleagues found that PAX5 and IKZF1, transcription factors that are critical for early B-cell development, “enforce a state of chronic energy deprivation” that results in constitutive activation of the energy-stress sensor AMPK.
However, dominant-negative mutants of PAX5 and IKZF1 reverse this effect.
Past research has suggested that mutations and deletions in the PAX5 and IKZF1 genes occur in more than 80% of cases of pre-B-cell acute lymphoblastic leukemia (ALL).
In the current study, Dr Müschen and his colleagues found that heterozygous deletion of Pax5 in a mouse model of pre-B ALL greatly increased glucose uptake and ATP levels.
Similarly, when they reconstituted PAX5 and IKZF1 in samples from patients with pre-B ALL, the investigators observed “an energy crisis” that prompted leukemic cell death.
Dr Müschen and his colleagues also performed a CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets. They said this revealed that NR3C1, TXNIP, and CNR2 are central effectors of B-lymphoid restriction of glucose and energy.
To build upon this finding, the investigators tested TXNIP and CNR2 agonists as well as a small-molecule AMPK inhibitor. They found these compounds synergized with glucocorticoids in patient-derived pre-B ALL cells.
The team therefore concluded that TXNIP, CNR2, and AMPK are potential therapeutic targets for pre-B ALL.
The investigators also said the results of this study support a previous finding that obese children with high blood sugar levels are much more likely to develop drug-resistant leukemia than children who are not overweight. So dieting could be an important consideration for children who have survived leukemia.
“Avoiding obesity and excessive energy supply may help to decrease the risk of leukemia relapse,” said study author Lai Chan, PhD, also of City of Hope.
To test that theory, Drs Chan and Müschen and their colleagues plan to perform experiments in animal models to evaluate the efficacy of dietary restriction on patient-derived childhood leukemia cells, and to assess the activity of drugs that reduce leukemia cells’ glucose and energy supply.
“Based on the outcome of these studies, we plan to introduce dietary restriction and/or glucose-restricting drugs into a clinical trial for children who are at risk to develop leukemia relapse,” Dr Müschen said.
