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

• Published in: Leukemia Vol. 29; no. 6; pp. 1320 - 1330
• Main Authors: Wang, L D, Rao, T N, Rowe, R G, Nguyen, P T, Sullivan, J L, Pearson, D S, Doulatov, S, Wu, L, Lindsley, R C, Zhu, H, DeAngelo, D J, Daley, G Q, Wagers, A J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2015
• Subjects: Abnormalities; Aged; Aged, 80 and over; Allergies; Animals; Autoimmunity; Blotting, Western; Bone Marrow Transplantation; Cancer research; Care and treatment; Cell Differentiation; Cell fate; Cell proliferation; Cells, Cultured; Cellular proteins; Critical components; Development and progression; Differentiation (biology); DNA-Binding Proteins - physiology; Female; Fetuses; Flow Cytometry; Gene expression; Genetic aspects; Genetic regulation; Health aspects; Hematological diseases; Hematopoiesis - physiology; Hemopoiesis; Humans; Immune response; Immune response regulation; Immune system; Innate immunity; Interrogation; Leukemia; Leukemia, Mast-Cell - metabolism; Leukemia, Mast-Cell - pathology; Leukemia, Mast-Cell - therapy; Male; Malignancy; Mast cell disease; Mast cells; Mast Cells - cytology; Mast Cells - metabolism; Mastocytosis; Mastocytosis, Systemic - metabolism; Mastocytosis, Systemic - pathology; Mastocytosis, Systemic - therapy; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Myeloid Cells - cytology; Myeloid Cells - metabolism; Organs; Peritoneum; Pluripotency; Properties; Real-Time Polymerase Chain Reaction; Regeneration; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA-Binding Proteins - metabolism; Tissue engineering; United States
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2015.19

Mast cells (MCs) are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration and tumor progression. Dysregulated MC development leads to systemic mastocytosis (SM), 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 MC 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-MC progenitors altering gene expression patterns to favor cell fate choices that enhanced MC specification. In addition, LIN28B-induced MCs appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of MC terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human MC leukemia samples revealed upregulation of LIN28B in abnormal MCs from patients with SM. This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in MC disease.