A Step-wise, Deterministic and Fatal Mouse Model of Myeloid Neoplasm with Spontaneous Acquisition of Patient-relevant RTK–RAS Mutations
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Leukaemia arises through the stepwise transformation of healthy haematopoietic cells, yet the asymptomatic premalignant phase and its progression to overt disease remain poorly understood. To model this process, we engineered a patient-derived CEBPA mutation into Hoxb8-FL multipotent murine progenitors and transplanted them into syngeneic mice, capturing a clinically silent premalignant stage. All recipients developed overt disease after ∼12 months with 100% penetrance and all acquired secondary RTK–RAS mutations, often with identical amino acid changes to those in patients. Single-cell transcriptomics and phenotypic profiling showed that premalignant mutant cells adopt a plasmacytoid dendritic progenitor–like state in vitro which generates both myeloid and B-lymphoid lineages during premalignancy in vivo, with individual tumours restricted to one lineage. Specificity for RTK-RAS mutations coupled with ongoing differentiation is reminiscent of Juvenile Myelomonocytic Leukaemia, where cellular models are currently lacking, thus providing a tractable model of myeloid neoplasm for mechanistic studies and drug discovery.
