1. Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis
- Author
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Sandeep Gurbuxani, John D. Crispino, William Vainchenker, Laure Gilles, Leonidas C. Platanias, Qiong Yang, Brady L. Stein, Katerina Konstantinoff, Qiang Jeremy Wen, Ahmet Dirim Arslan, Christian Marinaccio, Sriram Sundaravel, Maureen McNulty, Isabelle Plo, Priyanka Arya, Ayalew Tefferi, Amittha Wickrema, Anna Rita Migliaccio, Jonathan C. Zhao, Terra L. Lasho, Animesh Pardanani, Gilles, L, Arslan, Ad, Marinaccio, C, Wen, Qj, Arya, P, Mcnulty, M, Yang, Q, Zhao, Jc, Konstantinoff, K, Lasho, T, Pardanani, A, Stein, B, Plo, I, Sundaravel, S, Wickrema, A, FRANCO MIGLIACCIO, ANNA RITA, Gurbuxani, S, Vainchenker, W, Platanias, Lc, Tefferi, A, and Crispino, J. D.
- Subjects
Ribosomal Proteins ,0301 basic medicine ,CD34 ,Down-Regulation ,Biology ,Thrombopoiesis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Animals ,Humans ,Downregulation GATA1 hematopoiesis myelofibrosis ,GATA1 Transcription Factor ,Myelofibrosis ,Megakaryopoiesis ,Brief Report ,Myeloid leukemia ,GATA1 ,General Medicine ,medicine.disease ,Extramedullary hematopoiesis ,Haematopoiesis ,030104 developmental biology ,Primary Myelofibrosis ,030220 oncology & carcinogenesis ,Cancer research ,Chromosomes, Human, Pair 5 ,Chromosome Deletion ,Megakaryocytes - 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.
- Published
- 2017