title: The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy.
abstract: 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.
authors: 1] Department of Pathology, Joslin Diabetes Center, Boston, MA, USA [2] Harvard Stem Cell Institute, Cambridge, MA, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA [4] Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Center for Cancer and Blood Disorders, Boston, MA, USA [5] Department of Medicine, Boston Children's Hospital, Boston, MA, USA.
authors: L D
authors: LD
authors: Wang
authors: 1] Department of Pathology, Joslin Diabetes Center, Boston, MA, USA [2] Harvard Stem Cell Institute, Cambridge, MA, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
authors: T N
authors: TN
authors: Rao
authors: 1] Harvard Stem Cell Institute, Cambridge, MA, USA [2] Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Center for Cancer and Blood Disorders, Boston, MA, USA [3] Department of Medicine, Boston Children's Hospital, Boston, MA, USA [4] Manton Center for Orphan Disease Research, Boston, MA, USA [5] Howard Hughes Medical Institute, Boston, MA, USA.
authors: R G
authors: RG
authors: Rowe
authors: 1] Department of Pathology, Joslin Diabetes Center, Boston, MA, USA [2] Harvard Stem Cell Institute, Cambridge, MA, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
authors: P T
authors: PT
authors: Nguyen
authors: 1] Department of Pathology, Joslin Diabetes Center, Boston, MA, USA [2] Harvard Stem Cell Institute, Cambridge, MA, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
authors: J L
authors: JL
authors: Sullivan
authors: 1] Harvard Stem Cell Institute, Cambridge, MA, USA [2] Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Center for Cancer and Blood Disorders, Boston, MA, USA [3] Department of Medicine, Boston Children's Hospital, Boston, MA, USA [4] Manton Center for Orphan Disease Research, Boston, MA, USA [5] Howard Hughes Medical Institute, Boston, MA, USA [6] Medical Scientist Training Program, Harvard Medical School, Boston, MA, USA.
authors: D S
authors: DS
authors: Pearson
authors: 1] Harvard Stem Cell Institute, Cambridge, MA, USA [2] Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Center for Cancer and Blood Disorders, Boston, MA, USA [3] Department of Medicine, Boston Children's Hospital, Boston, MA, USA [4] Manton Center for Orphan Disease Research, Boston, MA, USA [5] Howard Hughes Medical Institute, Boston, MA, USA.
authors: S
authors: S
authors: Doulatov
authors: 1] Department of Pediatrics and Internal Medicine, Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Organ Transplant Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors: L
authors: L
authors: Wu
authors: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.
authors: R C
authors: RC
authors: Lindsley
authors: Department of Pediatrics and Internal Medicine, Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: H
authors: H
authors: Zhu
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: D J
authors: DJ
authors: DeAngelo
authors: 1] Harvard Stem Cell Institute, Cambridge, MA, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA [3] Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Center for Cancer and Blood Disorders, Boston, MA, USA [4] Department of Medicine, Boston Children's Hospital, Boston, MA, USA [5] Manton Center for Orphan Disease Research, Boston, MA, USA [6] Howard Hughes Medical Institute, Boston, MA, USA [7] Medical Scientist Training Program, Harvard Medical School, Boston, MA, USA [8] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors: G Q
authors: GQ
authors: Daley
authors: 1] Department of Pathology, Joslin Diabetes Center, Boston, MA, USA [2] Harvard Stem Cell Institute, Cambridge, MA, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA [4] Howard Hughes Medical Institute, Boston, MA, USA.
authors: A J
authors: AJ
authors: Wagers
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D007946:Leukemia, Mast-Cell / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D008297:Male; D008407:Mast Cells / Q000166:cytology* / Q000378:metabolism; D034721:Mastocytosis, Systemic / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; C570876:Lin28b protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins
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