title: Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis.
abstract: Primary myelofibrosis (PMF) is a clonal hematologic malignancy characterized by BM fibrosis, extramedullary hematopoiesis, circulating CD34+ cells, splenomegaly, and a propensity to evolve to acute myeloid leukemia. Moreover, the spleen and BM of patients harbor atypical, clustered megakaryocytes, which contribute to the disease by secreting profibrotic cytokines. Here, we have revealed that megakaryocytes in PMF show impaired maturation that is associated with reduced GATA1 protein. In investigating the cause of GATA1 downregulation, our gene-expression study revealed the presence of the RPS14-deficient gene signature, which is associated with defective ribosomal protein function and linked to the erythroid lineage in 5q deletion myelodysplastic syndrome. Surprisingly, reduced GATA1 expression and impaired differentiation were limited to megakaryocytes, consistent with a proproliferative effect of a GATA1 deficiency on this lineage. Importantly, expression of GATA1 effectively rescued maturation of PMF megakaryocytes. Together, these results suggest that ribosomal deficiency contributes to impaired megakaryopoiesis in myeloproliferative neoplasms.
authors.forename: Laure
authors.initials: L
authors.lastname: Gilles
authors.forename: Ahmet Dirim
authors.initials: AD
authors.lastname: Arslan
authors.forename: Christian
authors.initials: C
authors.lastname: Marinaccio
authors.forename: Qiang Jeremy
authors.initials: QJ
authors.lastname: Wen
authors.forename: Priyanka
authors.initials: P
authors.lastname: Arya
authors.forename: Maureen
authors.initials: M
authors.lastname: McNulty
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Zhao
authors.forename: Katerina
authors.initials: K
authors.lastname: Konstantinoff
authors.forename: Terra
authors.initials: T
authors.lastname: Lasho
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
authors.forename: Brady
authors.initials: B
authors.lastname: Stein
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
authors.forename: Sriram
authors.initials: S
authors.lastname: Sundaravel
authors.forename: Amittha
authors.initials: A
authors.lastname: Wickrema
authors.forename: Annarita
authors.initials: A
authors.lastname: Migliaccio
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D050982:GATA1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D055728:Primary Myelofibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012269:Ribosomal Proteins / Q000096:biosynthesis / Q000235:genetics; D034061:Thrombopoiesis
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; C526722:RPS14 protein, human; D012269:Ribosomal Proteins