title: Congenital amegakaryocytic thrombocytopenia iPS cells exhibit defective MPL-mediated signaling.
abstract: Congenital amegakaryocytic thrombocytopenia (CAMT) is caused by the loss of thrombopoietin receptor-mediated (MPL-mediated) signaling, which causes severe pancytopenia leading to bone marrow failure with onset of thrombocytopenia and anemia prior to leukopenia. Because Mpl(-/-) mice do not exhibit the human disease phenotype, we used an in vitro disease tracing system with induced pluripotent stem cells (iPSCs) derived from a CAMT patient (CAMT iPSCs) and normal iPSCs to investigate the role of MPL signaling in hematopoiesis. We found that MPL signaling is essential for maintenance of the CD34+ multipotent hematopoietic progenitor (MPP) population and development of the CD41+GPA+ megakaryocyte-erythrocyte progenitor (MEP) population, and its role in the fate decision leading differentiation toward megakaryopoiesis or erythropoiesis differs considerably between normal and CAMT cells. Surprisingly, complimentary transduction of MPL into normal or CAMT iPSCs using a retroviral vector showed that MPL overexpression promoted erythropoiesis in normal CD34+ hematopoietic progenitor cells (HPCs), but impaired erythropoiesis and increased aberrant megakaryocyte production in CAMT iPSC-derived CD34+ HPCs, reflecting a difference in the expression of the transcription factor FLI1. These results demonstrate that impaired transcriptional regulation of the MPL signaling that normally governs megakaryopoiesis and erythropoiesis underlies CAMT.
authors.affiliation: Clinical Application Department, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hirata
authors.forename: Naoya
authors.initials: N
authors.lastname: Takayama
authors.forename: Ryoko
authors.initials: R
authors.lastname: Jono-Ohnishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Endo
authors.forename: Sou
authors.initials: S
authors.lastname: Nakamura
authors.forename: Takeaki
authors.initials: T
authors.lastname: Dohda
authors.forename: Masanori
authors.initials: M
authors.lastname: Nishi
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Hamazaki
authors.forename: Ei-ichi
authors.initials: E
authors.lastname: Ishii
authors.forename: Shin
authors.initials: S
authors.lastname: Kaneko
authors.forename: Makoto
authors.initials: M
authors.lastname: Otsu
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.forename: Koji
authors.initials: K
authors.lastname: Eto
mesh_terms: D001792:Blood Platelets / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D000080984:Congenital Bone Marrow Failure Syndromes; D004912:Erythrocytes / Q000502:physiology; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008533:Megakaryocytes / Q000502:physiology; D020125:Mutation, Missense; D010641:Phenotype; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000502:physiology; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: C078433:FLI1 protein, human; D019038:Platelet Glycoprotein GPIb-IX Complex; D051789:Proto-Oncogene Protein c-fli-1; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human
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