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Haematologica. 2015 Apr;100(4):439-51. doi: 10.3324/haematol.2014.119537. Epub 2014 Dec 31.

Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology.

Author information

1
Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of the City of Hope, Duarte, CA, USA Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Japan.
2
Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of the City of Hope, Duarte, CA, USA Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3
Department of Cell Biology, Harvard Medical School, Boston, MA, USA Department of Pediatrics Harvard Medical School, Boston, MA, USA Program in Cellular & Molecular Medicine, Boston Children's Hospital, MA, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
5
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
6
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Department of Hematology, General Hospital of Chengdu Military Region, Chengdu, China.
7
Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
8
Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
9
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
10
Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of the City of Hope, Duarte, CA, USA Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA tmaeda@partners.org.

Abstract

Clathrin-dependent endocytosis is an essential cellular process shared by all cell types. Despite this, precisely how endocytosis is regulated in a cell-type-specific manner and how this key pathway functions physiologically or pathophysiologically remain largely unknown. PICALM, which encodes the clathrin adaptor protein PICALM, was originally identified as a component of the CALM/AF10 leukemia oncogene. Here we show, by employing a series of conditional Picalm knockout mice, that PICALM critically regulates transferrin uptake in erythroid cells by functioning as a cell-type-specific regulator of transferrin receptor endocytosis. While transferrin receptor is essential for the development of all hematopoietic lineages, Picalm was dispensable for myeloid and B-lymphoid development. Furthermore, global Picalm inactivation in adult mice did not cause gross defects in mouse fitness, except for anemia and a coat color change. Freeze-etch electron microscopy of primary erythroblasts and live-cell imaging of murine embryonic fibroblasts revealed that Picalm function is required for efficient clathrin coat maturation. We showed that the PICALM PIP2 binding domain is necessary for transferrin receptor endocytosis in erythroblasts and absolutely essential for erythroid development from mouse hematopoietic stem/progenitor cells in an erythroid culture system. We further showed that Picalm deletion entirely abrogated the disease phenotype in a Jak2(V617F) knock-in murine model of polycythemia vera. Our findings provide new insights into the regulation of cell-type-specific transferrin receptor endocytosis in vivo. They also suggest a new strategy to block cellular uptake of transferrin-bound iron, with therapeutic potential for disorders characterized by inappropriate red blood cell production, such as polycythemia vera.

PMID:
25552701
PMCID:
PMC4380716
DOI:
10.3324/haematol.2014.119537
[Indexed for MEDLINE]
Free PMC Article

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