Distinct stem cell identities converge into shared erythroid stress in ERCC6L2 disease and Shwachman–Diamond syndrome

Abstract ERCC6L2 disease (ED) is a rare bone marrow failure syndrome caused by biallelic germline mutations in ERCC6L2 . ED leads to the accumulation of somatic TP53 mutations, myelodysplastic syndrome, and acute myeloid leukemia (AML) with erythroid predominance and poor prognosis. While ERCC6L2 is implicated in DNA replication and repair, the transcriptomic events underlying delayed erythropoiesis and leukemic progression remain largely undefined. To delineate these processes, we leverage bulk and single‐cell transcriptomics of patient fibroblasts, bone marrow, and peripheral blood across disease stages, including single‐cell TP53 genotyping. We identify disease‐associated erythroid dysregulation and ferroptotic stress emerging prior to TP53 mutation, highlighting an early vulnerability in ED leukemogenesis. We compare ED to Shwachman–Diamond syndrome (SDS) to reveal shared and disease‐specific transcriptional programs. TP53 mutations in ED and SDS arise in hematopoietic stem and progenitor cells but do not independently drive changes in cell cycle or stress pathways during erythropoiesis, despite harboring distinct germline defects. Both diseases converge in late erythropoiesis into a stress state characterized by ferroptotic signaling, G1 arrest, and BCL2L1 upregulation. As a disease‐specific pattern, ED shows aberrant erythroid priming with TP53 ‐driven differentiation arrest shaping progression toward erythroid leukemia. Thereby, we establish the first patient‐level single‐cell map of ED and provide a curated resource for future work on ED, SDS, and TP53 ‐driven leukemogenesis. Overall, our findings in pre‐malignant ED offer a window into early alterations leading to high‐risk leukemia.