Many documented predisposing loci continued to lack functional characterization even though the World Health Organization classified hereditary myeloid malignancies as distinct entities. While germline mutations in the DNA repair factor ERCC excision repair 6 like 2 (ERCC6L2) cause acute myeloid leukemia and bone marrow failure, the effects on normal hematopoiesis were unknown. To functionally characterize the dual impacts of germline ERCC6L2 loss on human primary hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs), researchers, ex vivo challenged ERCC6L2-silenced and patient-derived cells. 

For a study, they demonstrated for the first time that HSPCs with ERCC6L2-deficiency have considerably reduced clonogenic capacity and delayed erythroid differentiation. The finding was supported by CIBERSORTx RNA-sequencing deconvolution on erythroid-committed cells silenced for ERCC6L2, which showed increased proportions of polychromatic erythroblasts and decreased orthochromatic erythroblasts compared to controls. 

By observing a dramatic phenotype in patient-derived and ERCC6L2-silenced MSCs, which display accelerated osteogenesis and decreased adipogenesis, they also showed that the effects of ERCC6L2-deficiency were not restricted to HSPCs. 

Overall, the data showed the significance of considering the impact of germline mutations in HSPCs and their microenvironment and presented a useful surrogate model to explore the impact of inherited myeloid mutations.

Reference: onlinelibrary.wiley.com/doi/10.1111/bjh.18466