Bone marrow failure, somatic rescue by p53 inactivation, and enhanced leukemogenesis in germline ERCC6L2 disease

Altogether, loss of Ercc6l2 leads to reduced HSPC numbers, bone marrow hypocellularity, and cytopenias. Notably, somatic Trp53 mutations restore cellular fitness of Ercc6l2-deficient HSPCs by abrogating p53 pathway activation and restoring Runx1 and Gata1 expression, thereby correcting the BMF phenotype. However, p53 loss fails to normalize replication stress, allowing for the accumulation of DNA damage over time which increases the likelihood for leukemic transformation.

Our data uncover the pathogenesis of ERCC6L2 disease and provide a prototypic example of clonal compensation in BMF syndromes, where somatic mutations in leukemia-associated genes – in this case TP53 – transiently improve blood cell production at, however, the expense of increasing leukemogenic potential.