Distinct Stem Cell Identities Converge into Shared Erythroid Stress in ERCC6L2 Disease and Shwachman-Diamond Syndrome

ERCC6L2 disease (ED) is a rare bone marrow failure syndrome caused by biallelic germline mutations in ERCC6L2 . ED leads to accumulation of somatic TP53 mutations, myelodysplastic syndrome, and acute myeloid leukemia (AML) with erythroid predominance and poor prognosis. Given the global challenge of treating TP53 -mutated AML, ED provides a unique opportunity to study early events leading to high-risk leukemia. 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 delay 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. 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 and a differentiation block in TP53 -mutated cells during leukemic transformation.

Taken together, we provide the first single-cell analyses in ED, define stress responses shared with SDS, and aberrant erythroid priming with TP53 -driven differentiation arrest shaping progression toward erythroid leukemia. Our results give biological insights to guide therapy development aiming at intercepting disease evolution to treatment-refractory AML.