In this issue of Blood, Schimmer et al 1 demonstrate that p53 loss can rescue bone marrow failure (BMF) phenotypes caused by biallelic mutations in ERCC6L2 but at the cost of profound genome instability, leading to the onset of aggressive erythroid leukemia.Germ line homozygous loss-offunction mutations in ERCC6L2 have now been described in over 100 patients to cause BMF with onset in young adulthood and a high risk of transformation to myelodysplastic syndromes and acute myeloid leukemia, which present almost uniformly (>90%) with biallelic TP53 mutations in these patients. 23]4 This association with TP53 mutation is far greater than in general myeloid malignancy cohorts and is also greater than in patients with other inherited BMF syndromes, such as Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and the short telomere syndromes, all of which are associated with p53-related mechanisms. 5Thus, the profoundly high rate of occurrence of TP53 mutations in patients with ERCC6L2, even compared to these other syndromes, is a remarkable observation that likely indicates a specific biologic dependence.Prior reports that TP53 mutation precedes the development of malignancy in patients with ERCC6L2, often by many years, 2 provide context for the novel findings by Schimmer et al indicating that p53 loss in ERCC6L2-deficient hematopoietic stem and progenitor cells (HSPC) provides short-term benefits for hematopoiesis but evetually leads to transformation.
Timothy M. Chlon (Thu,) studied this question.