Photo by Petr Kratochvil
Whole-exome sequencing has provided new insights that may lead to better treatment of juvenile myelomonocytic leukemia (JMML), according to researchers.
The group identified new mutations that appear to drive JMML and could be targeted with drugs that are currently available, such as JAK inhibitors.
The study also suggests it is the number of mutations a patient has—and not the type of mutations—that will influence the patient’s outcome.
Researchers reported these discoveries in Nature Genetics.
“We’ve created the most comprehensive portrait yet of how this cancer evolves from first diagnosis through remission or relapse,” said study author Mignon Loh, MD, of Benioff Children’s Hospital at University of California, San Francisco (USCF). “What we found helps make sense of why patients’ outcomes have been so wildly different.”
“We have personally treated patients with JMML at UCSF with identical driver mutations, some of whom survived, while others died,” added Elliot Stieglitz, MD. “Our frustration was the main impetus that led us to carry out this study.”
So the researchers performed whole-exome sequencing on samples collected at diagnosis and relapse in 27 JMML patients who were 1 month to 3 years of age. The team then performed targeted sequencing of suspected mutation hot spots in another 71 patients.
Previously, just 5 defects in the Ras pathway had been associated with JMML. The new analysis added 10 mutations of known oncogenes and tumor suppressors to the list, including 2 additional Ras pathway genes.
These newly identified mutations occur in genes coding for proteins that function as signaling molecules, transcription factors, epigenetic regulators, and elements of the spliceosome complex.
Several of these mutations raise the possibility of targeting subpopulations of JMML cases with existing drugs.
For instance, JAK inhibitors might inhibit signaling through a hyperactive JAK-STAT pathway identified in some patients. And 5-azacytidine could be used to reduce excessive epigenetic DNA methylation seen in others.
The researchers also performed a 10-year survival study with the same participants and found that patients’ prognosis depended more on the number of mutations they had than on the specific mutations involved.
Patients with more than 1 mutation at the time of diagnosis had a significantly worse long-term prognosis. Of the 34 patients who had at least 2 mutations, only 29% survived for 10 years, compared to a 65% survival rate for patients who had 1 or fewer detectable mutations.
“We have now shown that while driver mutations in the Ras pathway likely cause the leukemia to develop in the first place, it is the presence of these additional mutations that contribute to poor outcome,” Dr Loh said, noting that therapies will likely require targeting multiple pathways at once.
“Precisely how these secondary mutations will interact with the Ras pathway is the focus of our ongoing work.”
