By undertaking a comprehensive characterization of the transcriptomiclandscapes across all stages of tumor cell development in Ptpn11mutation-associated JMML and substantiating our findings through experimental validation, wehave discovered that Ptpn11-mutated stem cells (leukemia-initiating cells)are primed by the myeloid transcriptional program and that innate immune and inflammatoryresponses are aberrantly activated in these cells. The gene discussed is PTPN11; the disease is juvenile myelomonocytic leukemia.