The genomic landscape of juvenile myelomonocytic leukemia

The genomic landscape of juvenile myelomonocytic leukemia

Stieglitz, E, 2015, Nature Genetics  (Link to abstract)                                                            

Previous studies have characterized JMML as “Rasopathy”, mostly driven by activation of the Ras-MAPK pathway through mutations in NF1, NRAS, KRAS, PTPN11 or CBL. Seeking to understand the mutational landscape of JMML and identify additional pathways involved in disease initiation and progression, the authors performed whole-exome sequencing in serial samples from patients at diagnosis, relapse and transformation to AML.

In addition to known genetic hits, the group identified 2 new mutations in the Ras-MAPK pathway (SH2B3 and RRAS2), as well as activation of JAK-STAT signaling and epigenetic modification through the PRC2 and spliceosome complexes as important in leukemogenesis in JMML. In 16/22 patients that were analyzed over time, the mutations identified at diagnosis were invariably maintained at relapse. Several mutated genes, previously unknown to be implicated in JMML, were identified at relapse (JAK3 and RUNX1).

Contrary to previous reports, they found no difference in outcome between patients harboring different somatic mutations; when corrected for other variables, the number - rather than the type - of mutations at diagnosis was the main determinant of outcome.

* JMML is more than a Rasopathy and the discovery of additional molecular alterations provides rationale for new therapeutic approaches (such as demethylating agents[NW2] ) and better patient stratification.