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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 2

RPS14 is required for megakaryocyte maturation.

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RPS14 is required for megakaryocyte maturation.
(A) Fold change in expre...
(A) Fold change in expression of myeloid genes in megakaryocytes derived from PMF specimens or healthy control CD34+ cells. Results were derived from the gene-expression arrays. (B) GSEA analysis revealed that the RPS14_DN.V1_UP pathway (RPS14 gene signature) is significantly enriched. NES, normalized enrichment score; FDR, false discovery rate. (C) CD34+ cells were transduced with a control lentivirus or a lentivirus encoding either shRPS14 G5 or shRPS14 G8 and cultured under megakaryocytic differentiation conditions including 10 ng/ml THPO. Two representative experiments of 3 are shown. Megakaryocyte differentiation was reduced by 47% ± 24% in the presence of shRPS14. n = 3. P = 0.03, Student’s t test. (D) Protein synthesis assay comparing PMF megakaryocytes with controls. Top panel: flow cytometry analysis of OP-PURO fluorescence in control versus PMF 28 CD42+ megakaryocytes. Bottom panel: mean OP-Puro fluorescence intensity for controls versus PMF samples.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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