June 2024—Somatic mutations in SETBP1 occur in a variety of myeloid malignancies, including myelodysplastic/myeloproliferative neoplasms, typically as secondary events during oncogenesis. However, whether SETBP1 alterations can serve as an initiating event for myeloid neoplasia and what other factors may influence the phenotype of SETBP1-mutated myeloid neoplasms remains unclear. To determine if SETBP1 mutations can initiate leukemia in vivo, the authors generated a mouse model expressing mutated SETBP1 in hematopoietic tissue. They reported that SETBP1G870S-mutated mice developed a chronic myeloid disorder with massive hepatosplenomegaly, myelofibrosis, atypical megakaryocytes, and granulocytic hyperplasia without granulocytic or erythroid dysplasia. SETBP1G870S precursors showed significant alterations in the transcriptional programs of differentiating hematopoietic cells, promoting granulocytic/monocytic differentiation while suppressing erythroid differentiation.