Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis

Laure Gilles, Ahmet Dirim Arslan, Christian Marinaccio, Qiang Jeremy Wen, Priyanka Arya, Maureen McNulty, Qiong Yang, Jonathan C. Zhao, Katerina Konstantinoff, Terra Lasho, Animesh D Pardanani, Brady Stein, Isabelle Plo, Sriram Sundaravel, Amittha Wickrema, Annarita Migliaccio, Sandeep Gurbuxani, William Vainchenker, Leonidas C. Platanias, Ayalew Tefferi & 1 others John D. Crispino

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1316-1320
Number of pages5
JournalJournal of Clinical Investigation
Volume127
Issue number4
DOIs
StatePublished - Apr 3 2017

Fingerprint

Primary Myelofibrosis
Megakaryocytes
Hematopoiesis
Down-Regulation
Extramedullary Hematopoiesis
Ribosomal Proteins
Myelodysplastic Syndromes
Splenomegaly
Hematologic Neoplasms
Acute Myeloid Leukemia
Fibrosis
Spleen
Cytokines
Gene Expression
Genes
Neoplasms
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gilles, L., Arslan, A. D., Marinaccio, C., Wen, Q. J., Arya, P., McNulty, M., ... Crispino, J. D. (2017). Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis. Journal of Clinical Investigation, 127(4), 1316-1320. https://doi.org/10.1172/JCI82905

Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis. / Gilles, Laure; Arslan, Ahmet Dirim; Marinaccio, Christian; Wen, Qiang Jeremy; Arya, Priyanka; McNulty, Maureen; Yang, Qiong; Zhao, Jonathan C.; Konstantinoff, Katerina; Lasho, Terra; Pardanani, Animesh D; Stein, Brady; Plo, Isabelle; Sundaravel, Sriram; Wickrema, Amittha; Migliaccio, Annarita; Gurbuxani, Sandeep; Vainchenker, William; Platanias, Leonidas C.; Tefferi, Ayalew; Crispino, John D.

In: Journal of Clinical Investigation, Vol. 127, No. 4, 03.04.2017, p. 1316-1320.

Research output: Contribution to journalArticle

Gilles, L, Arslan, AD, Marinaccio, C, Wen, QJ, Arya, P, McNulty, M, Yang, Q, Zhao, JC, Konstantinoff, K, Lasho, T, Pardanani, AD, Stein, B, Plo, I, Sundaravel, S, Wickrema, A, Migliaccio, A, Gurbuxani, S, Vainchenker, W, Platanias, LC, Tefferi, A & Crispino, JD 2017, 'Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis', Journal of Clinical Investigation, vol. 127, no. 4, pp. 1316-1320. https://doi.org/10.1172/JCI82905
Gilles L, Arslan AD, Marinaccio C, Wen QJ, Arya P, McNulty M et al. Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis. Journal of Clinical Investigation. 2017 Apr 3;127(4):1316-1320. https://doi.org/10.1172/JCI82905
Gilles, Laure ; Arslan, Ahmet Dirim ; Marinaccio, Christian ; Wen, Qiang Jeremy ; Arya, Priyanka ; McNulty, Maureen ; Yang, Qiong ; Zhao, Jonathan C. ; Konstantinoff, Katerina ; Lasho, Terra ; Pardanani, Animesh D ; Stein, Brady ; Plo, Isabelle ; Sundaravel, Sriram ; Wickrema, Amittha ; Migliaccio, Annarita ; Gurbuxani, Sandeep ; Vainchenker, William ; Platanias, Leonidas C. ; Tefferi, Ayalew ; Crispino, John D. / Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 4. pp. 1316-1320.
@article{dea3a5bca5254221b14e53840de4be03,
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.",
author = "Laure Gilles and Arslan, {Ahmet Dirim} and Christian Marinaccio and Wen, {Qiang Jeremy} and Priyanka Arya and Maureen McNulty and Qiong Yang and Zhao, {Jonathan C.} and Katerina Konstantinoff and Terra Lasho and Pardanani, {Animesh D} and Brady Stein and Isabelle Plo and Sriram Sundaravel and Amittha Wickrema and Annarita Migliaccio and Sandeep Gurbuxani and William Vainchenker and Platanias, {Leonidas C.} and Ayalew Tefferi and Crispino, {John D.}",
year = "2017",
month = "4",
day = "3",
doi = "10.1172/JCI82905",
language = "English (US)",
volume = "127",
pages = "1316--1320",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

TY - JOUR

T1 - Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis

AU - Gilles, Laure

AU - Arslan, Ahmet Dirim

AU - Marinaccio, Christian

AU - Wen, Qiang Jeremy

AU - Arya, Priyanka

AU - McNulty, Maureen

AU - Yang, Qiong

AU - Zhao, Jonathan C.

AU - Konstantinoff, Katerina

AU - Lasho, Terra

AU - Pardanani, Animesh D

AU - Stein, Brady

AU - Plo, Isabelle

AU - Sundaravel, Sriram

AU - Wickrema, Amittha

AU - Migliaccio, Annarita

AU - Gurbuxani, Sandeep

AU - Vainchenker, William

AU - Platanias, Leonidas C.

AU - Tefferi, Ayalew

AU - Crispino, John D.

PY - 2017/4/3

Y1 - 2017/4/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85018710687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018710687&partnerID=8YFLogxK

U2 - 10.1172/JCI82905

DO - 10.1172/JCI82905

M3 - Article

VL - 127

SP - 1316

EP - 1320

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -