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

L D Wang; T N Rao; R G Rowe; P T Nguyen; J L Sullivan; D S Pearson; S Doulatov; L Wu; R C Lindsley; H Zhu; D J DeAngelo; G Q Daley; A J Wagers

doi:10.1038/leu.2015.19

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

Leukemia. 2015 Jun;29(6):1320-30. doi: 10.1038/leu.2015.19. Epub 2015 Feb 6.

Authors

L D Wang¹, T N Rao², R G Rowe³, P T Nguyen², J L Sullivan², D S Pearson⁴, S Doulatov³, L Wu⁵, R C Lindsley⁶, H Zhu⁷, D J DeAngelo⁸, G Q Daley⁹, A J Wagers¹⁰

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Department of Pediatrics and Internal Medicine, Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ 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.
¹⁰ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Animals
Blotting, Western
Bone Marrow Transplantation
Cell Differentiation*
Cells, Cultured
DNA-Binding Proteins / physiology*
Female
Flow Cytometry
Hematopoiesis / physiology
Humans
Leukemia, Mast-Cell / metabolism
Leukemia, Mast-Cell / pathology*
Leukemia, Mast-Cell / therapy
Male
Mast Cells / cytology*
Mast Cells / metabolism
Mastocytosis, Systemic / metabolism
Mastocytosis, Systemic / pathology*
Mastocytosis, Systemic / therapy
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Myeloid Cells / cytology*
Myeloid Cells / metabolism
RNA, Messenger / genetics
RNA-Binding Proteins / metabolism*
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction

Substances

DNA-Binding Proteins
LIN28B protein, human
Lin28b protein, mouse
RNA, Messenger
RNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding