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Secondary Mutations in JMML Linked to Disease Progression

NEW YORK (GenomeWeb News) – Using whole-exome sequencing, researchers in Japan have linked secondary mutations in two genes with disease progression in a subpopulation of juvenile myelomonocytic leukemia cases.

Seiji Kojima, a professor at Nagoya University Graduate School of Medicine, and his colleagues reported in Nature Genetics yesterday that the SETBP1 and JAK3 genes were common targets of secondary mutations in the childhood-onset disease. Mutations in those genes were further associated with poor outcomes.

"Mutations of SETBP1 and JAK3 were common recurrent secondary events presumed to be involved in tumor progression and were associated with poor clinical outcomes," Kojima and colleagues wrote. "Our findings provide an important clue to understanding the pathogenesis of JMML that may help in the development of novel diagnostics and therapeutics for this leukemia."

Juvenile myelomonocytic leukemia, or JMML, is marked by somatic and germline mutations affecting the RAS pathway — including NF1, NRAS, KRAS, PTPN11, and CBL — but other mutations associated with the disease and its development or progression are not as well understood.

To characterize gene mutations found in this disease, Kojima and his colleagues sequenced the whole exomes of tumor-normal pairs from 13 people with JMML, to 137x coverage for tumor samples and 143x coverage for normal samples. This, they estimated, captured 88 percent of somatic mutations.

Focusing on 25 candidate genes that were subject to Sanger sequencing, the researchers uncovered 11 non-silent somatic mutations, six of which were known to be involved in RAS pathways — RAS pathway mutations were seen, they noted, in 11 of the 13 cases.

The five non-RAS pathway mutations were traced to SETBP1, JAK3, and SHEBP1. SETBP1 encodes a protein that interacts with SET, which, in turn, inhibits two putative tumor suppressor proteins. Alterations to SETBP1 have also been linked to leukemias. For example, overexpression of SETBP1 is found in more than 27 percent of adult acute myeloid leukemia and is associated with poor survival, the researchers noted. Additionally, the JAK-STAT signaling pathway is involved in normal hematopoiesis.

Using deep sequencing, the researchers validated their findings by screening 92 JMML cases for the three new genes and other, known RAS pathway mutation targets. RAS mutations were found in nearly 90 percent of cases.

In addition, the researchers uncovered a number of mutations in SETBP1 or JAK3 in 16 of the 92 cases. Such secondary mutations, they noted, were more commonly found in cases that also had certain RAS mutations, like in PTPN11.

All of the SETBP1 mutations were heterozygous and located within the SKI-encoding domain, and eight of the 11 JAK3 mutations were activating mutations that have been identified in other blood malignancies such as Down syndrome-associated acute megakaryoblastic leukemia and acute lymphoblastic leukemia.

For the two cases in the discovery set that did not have the hallmark RAS pathway mutations, Kojima and his colleagues searched for possible germline mutations that could have led to JMML development. They found roughly 170 candidate germline mutations in each case, though none of those genes were known to affect the RAS or other cancer pathways. In addition, a portion of the validation cohort also lacked RAS-related mutations, leading the researchers to consider that those cases may represent a distinct disease.

Additionally, individuals with secondary JMML mutations had shorter survival times than those who did not have such mutations, the researchers said. Of the cohort members who survived without hematopoietic stem cell transplants, none had secondary mutations — individuals with secondary mutations had worse five-year transplant-free survival rates.

The secondary mutations may also present therapeutic targets. For example, the researchers said, "[t]argeting the JAK-STAT pathway with a pan-JAK inhibitor such as CP-690550 could be a promising therapeutic possibility for patients with JAK3-mutated JMML."