Scientists have developed a test that can predict how patients with juvenile myelomonocytic leukemia (JMML) will respond to treatment, and may also be able to identify patients who are likely to recover spontaneously with little to no treatment. The researchers are currently optimizing the test for more routine clinical use in the United States.

JMML is an aggressive leukemia that strikes approximately 50 children in the United States each year, typically under the age of four. The only known treatment is bone marrow transplant, an intensive therapy with serious long-term side effects. Unfortunately, transplants are only effective in half of all patients, with the other 50 percent relapsing within a few years. On the other hand, in rare cases, children with JMML have been known to spontaneously go into remission, but until now, no one had been able to predict at diagnosis which patients will have these radically divergent outcomes.

In a new study, published in Nature Communications, researchers have discovered that epigenetic annotations of the genome -- chemical "tags" that affect whether, how, and when particular genes are expressed -- can predict how children with JMML will respond to treatment. Using these tags as biomarkers could for the first time allow oncologists to make more informed treatment plans for these children. However, the study also emphasizes that many patients are unlikely to ever benefit from currently available treatments, and highlights a pressing need to develop new targeted therapies.
"This data provides important information that will help clinicians decide how intensively and swiftly to treat their patients," said senior author.

Previous studies by the team had shown that the number of mutations in a handful of key genes could help predict long-term outcomes for JMML patients, but in many patients, mutations alone did not seem able to explain why patients were having such different responses to treatment.

"We would see two different 2-year-olds with the exact same mutation, but one patient would relapse shortly after transplant, while the other would be cured, " said one of three co-first authors on the new study.

Lacking a genetic explanation for these variable patient outcomes, the researchers turned to epigenetics -- patterns of chemical annotations that cells use to adjust how and when genes are turned on and off. The researchers focused on one type of epigenetic tag -- DNA methylation -- which is known to be involved in controlling stem cell maturation in children and adults, and therefore seemed a likely candidate to impact outcomes in leukemia.

The team studied genome-wide methylation levels in an initial group of 39 patients with JMML, and then validated their results in an additional group of 40 patients treated in Germany. Statistical analysis revealed that patients fell into three groups, with high, intermediate, or low levels of DNA methylation. Furthermore, they found that patients' methylation levels mapped closely onto their treatment outcomes: relapse occurred in 70 percent of patients with the highest methylation scores (21/30), 41 percent of patients with intermediate methylation scores (9/22), and only 3 percent of patients with the lowest methylation scores (1/29).

"For us this was surprising," author said. "We are not yet able to say why DNA methylation is different amongst these patients, but for it to be so predictive of outcomes, even more than genetic mutations, was a big surprise."

Low methylation predicts spontaneous recovery. The results also suggested a biomarker for the rare cases of JMML patients who have spontaneously gone into remission. Why some children might spontaneously recover from this otherwise deadly disease had always been a mystery, but when the team examined these patients' methylation levels using their new test, they found that 14 of the 15 known cases of spontaneous recovery mapped closely onto the low-methylation group (and closest to healthy control subjects).

These findings suggest an urgent need for further study to design and validate the new methylation test for use in the clinic in order to identify children who could benefit from a watch-and-wait approach rather than rushing to perform risky bone marrow transplants, author said. They are currently working to validate their methylation test for clinical use at UCSF and in clinics around the world.

"Because we have never been able to tell which patients might spontaneously recover, and because the disease can be so aggressive, the standard of care has been to recommend transplants for everybody," auhtor said. "There are many health risks associated with bone marrow transplants, ranging from infections to long-term short stature, and even death in some cases. To be able to avoid this intensive intervention for some patients based on a methylation assay would really be cutting-edge clinical science."
 
https://www.ucsf.edu/news/2017/12/409481/dna-annotations-predict-patient-outcomes-childhood-leukemia

https://www.nature.com/articles/s41467-017-02178-9