Back to the roots – multi-omics as a road atlas to the cell-of-origin in rare childhood leukemia

JMML is a disease with divergent clinical characteristics. A small set of known genetic drivers cannot explain the clinical heterogeneity. We have recently described that distinct DNA methylation patterns characterise three different subgroups that correlate with prognosis. We hypothesise that different cellular origins determine the phenotypic heterogeneity of those subgroups. Therefore, we established an elaborate multi-omics approach for characterising the molecular and cellular heterogeneity underlying the pathogenesis of JMML. Epigenetic profiling reveals that differential methylation already exists in hematopoietic stem cells (HSCs), suggesting leukemia initiating cells on top of the hematopoietic hierarchy. Single-cell transcriptomics confirm the distinct nature of HSCs across subgroups, however, reasons for the clinical heterogeneity remain elusive. Strikingly, comparative DNA methylome analyses reveal distinct developmental signatures across patients, suggesting that the course of disease is significantly affected by the developmental origin of JMML. As a result, we are expanding our studies by generating a developmental DNA methylome atlas of healthy foetal to adult HSCs.

Publication History

Article published online:
17 May 2022