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Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis
Laure Gilles, … , Ayalew Tefferi, John D. Crispino
Laure Gilles, … , Ayalew Tefferi, John D. Crispino
Published February 27, 2017
Citation Information: J Clin Invest. 2017;127(4):1316-1320. https://doi.org/10.1172/JCI82905.
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Brief Report Hematology

Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis

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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

Laure Gilles, Ahmet Dirim Arslan, Christian Marinaccio, Qiang Jeremy Wen, Priyanka Arya, Maureen McNulty, Qiong Yang, Jonathan C. Zhao, Katerina Konstantinoff, Terra Lasho, Animesh Pardanani, Brady Stein, Isabelle Plo, Sriram Sundaravel, Amittha Wickrema, Annarita Migliaccio, Sandeep Gurbuxani, William Vainchenker, Leonidas C. Platanias, Ayalew Tefferi, John D. Crispino

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Figure 3

Restoration of GATA1 rescues the differentiation of PMF megakaryocytes.

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Restoration of GATA1 rescues the differentiation of PMF megakaryocytes.
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(A) Sucrose gradient polysome profiling showed a reduction in the 40S peak in SET2 cells overexpressing shRPS14 G5 or shRPS14 G8. The 40S, 60S, 80S, and ribosomal complexes are labeled. (B) Histogram showing the reduction in the ratio of 40S:60S subunits in the presence of 2 RPS14 shRNAs. Bar graph depicts mean ± SD of 2 biological replicates. (C) qRT-PCR showing the fold change in RPS14 expression upon knockdown (left) and GATA1 mRNA abundance in polysomes compared with monosomes (right). Data were normalized to GAPDH. Three biological replicates are shown. (D) GATA1 was overexpressed in CD34+ from PMF patients (PMF 21 and PMF 22). The numbers in red refer to the percentages of CD41+CD42+ cells or the percentages of cells with DNA content of 8 N or more. Two representative experiments of 3 are shown. FC, fold change.
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