Integrated molecular profiling of juvenile myelomonocytic leukemia

Integrated molecular profiling of juvenile myelomonocytic leukemia
JMML is a rare myeloid neoplasm with few therapeutic options. The majority of cases are driven by mutations in the RAS pathway and several molecular and clinical prognostic markers are known. This research group used multi-omic profiling to find driver events in the ~20% of patients without RAS mutations and to identify new prognostic markers.
150 children were included in this study although not all patients were evaluated by each modality. The majority of data was generated through high-throughput exome sequencing, high-throughput mRNA sequencing, and a DNA methylation array (the now-defunct Illumina 450K array).
1) Three children without RAS pathway mutations were found to have ALK (n = 2) or ROS1 (n = 1) fusions. Crizotinib (a TKI effective against ALK and ROS1 activity) decreased proliferation in cell lines obtained from these patients. One patient with an ALK fusion and refractory disease had a clinical response to Crizotinib bridging her to transplant.
2) The group identified 2 DNA methylation profiles and 4 RNA expression profiles. LIN28B (a developmental gene involved in microRNA activity and affected in multiple cancers) was both differentially methylated and expressed. The "hypermethylation" profile and "AML-like" profile both carried poor prognosis.
When creating tumor profiles using genome-wide data such as DNA methylation or RNA sequencing, investigators must make many choices (e.g. how to normalize and filter the data, which coordinates to use, how to define a subgroup etc). In this study, the selected sequencing methodology is debatable, so analyses can only be considered robust if they are convincingly replicated - otherwise they may be artifacts of upstream analytical decisions
This is a thorough analysis of a large number of JMML cases. The finding of ALK/ROS1 fusions - even though rare - should prompt us to look for these fusions in our refractory patients keeping in mind the possible use of targeted agents. The DNA methylation and expression profiles require replication before integration with clinical decision making.

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