The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

Mast cells are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration, and tumor progression. Dysregulated mast cell development leads to systemic mastocytosis, a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused mast cell accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil-mast cell progenitors altering gene expression patterns to favor cell fate choices that enhanced mast cell specification. In addition, LIN28B-induced mast cells appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of mast cell terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human mast cell leukemia samples revealed upregulation of LIN28B in abnormal mast cells from patients with systemic mastocytosis (SM). This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in mast cell disease.