The thrombopoietin/MPL axis is activated in the Gata1mouse model of myelofibrosis and is associated with a defective RPS14 signature

M Zingariello, L Sancillo, F Martelli, F Ciaffoni, M Marra, L Varricchio, R A Rana, C Zhao, J D Crispino, A R Migliaccio

Research output: Contribution to journalArticle

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Abstract

Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1lowmutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1lowmice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1lowLSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice. Gata1lowmarrow and spleen contained more JAK2/STAT5 than wild-type tissues, an indication that these organs were reach of TPO-responsive cells. Moreover, treatment of Gata1lowmice with the JAK inhibitor ruxolitinib reduced their splenomegaly. Also in Gata1lowmice activation of the TPO/MPL axis was associated with a RSP14 deficiency and a discordant microarray ribosome signature (reduced RPS24, RPS26 and SBDS expression). Finally, electron microscopy revealed that Gata1lowmegakaryocytes contained poorly developed endoplasmic reticulum with rare polysomes. In summary, Gata1lowmice are a bona fide model of MF, which recapitulates the hyperactivation of the TPO/MPL/JAK2 axis observed in megakaryocytes from myelofibrotic patients.

Original languageEnglish
Pages (from-to)e572
JournalBlood Cancer Journal
Volume7
Issue number6
DOIs
Publication statusPublished - Jun 16 2017

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Thrombopoietin
Primary Myelofibrosis
Megakaryocytes
Messenger RNA
Polyribosomes
Splenomegaly
Protein Biosynthesis
Ribosomes
Endoplasmic Reticulum
Electron Microscopy
Spleen
Liver

Keywords

  • Animals
  • Disease Models, Animal
  • Female
  • GATA1 Transcription Factor/genetics
  • Humans
  • Male
  • Mice
  • Primary Myelofibrosis/genetics
  • Ribosomal Proteins/genetics
  • Thrombopoietin/metabolism

Cite this

The thrombopoietin/MPL axis is activated in the Gata1mouse model of myelofibrosis and is associated with a defective RPS14 signature. / Zingariello, M; Sancillo, L; Martelli, F; Ciaffoni, F; Marra, M; Varricchio, L; Rana, R A; Zhao, C; Crispino, J D; Migliaccio, A R.

In: Blood Cancer Journal, Vol. 7, No. 6, 16.06.2017, p. e572.

Research output: Contribution to journalArticle

Zingariello, M ; Sancillo, L ; Martelli, F ; Ciaffoni, F ; Marra, M ; Varricchio, L ; Rana, R A ; Zhao, C ; Crispino, J D ; Migliaccio, A R. / The thrombopoietin/MPL axis is activated in the Gata1mouse model of myelofibrosis and is associated with a defective RPS14 signature. In: Blood Cancer Journal. 2017 ; Vol. 7, No. 6. pp. e572.
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abstract = "Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1lowmutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1lowmice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1lowLSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice. Gata1lowmarrow and spleen contained more JAK2/STAT5 than wild-type tissues, an indication that these organs were reach of TPO-responsive cells. Moreover, treatment of Gata1lowmice with the JAK inhibitor ruxolitinib reduced their splenomegaly. Also in Gata1lowmice activation of the TPO/MPL axis was associated with a RSP14 deficiency and a discordant microarray ribosome signature (reduced RPS24, RPS26 and SBDS expression). Finally, electron microscopy revealed that Gata1lowmegakaryocytes contained poorly developed endoplasmic reticulum with rare polysomes. In summary, Gata1lowmice are a bona fide model of MF, which recapitulates the hyperactivation of the TPO/MPL/JAK2 axis observed in megakaryocytes from myelofibrotic patients.",
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T1 - The thrombopoietin/MPL axis is activated in the Gata1mouse model of myelofibrosis and is associated with a defective RPS14 signature

AU - Zingariello, M

AU - Sancillo, L

AU - Martelli, F

AU - Ciaffoni, F

AU - Marra, M

AU - Varricchio, L

AU - Rana, R A

AU - Zhao, C

AU - Crispino, J D

AU - Migliaccio, A R

PY - 2017/6/16

Y1 - 2017/6/16

N2 - Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1lowmutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1lowmice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1lowLSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice. Gata1lowmarrow and spleen contained more JAK2/STAT5 than wild-type tissues, an indication that these organs were reach of TPO-responsive cells. Moreover, treatment of Gata1lowmice with the JAK inhibitor ruxolitinib reduced their splenomegaly. Also in Gata1lowmice activation of the TPO/MPL axis was associated with a RSP14 deficiency and a discordant microarray ribosome signature (reduced RPS24, RPS26 and SBDS expression). Finally, electron microscopy revealed that Gata1lowmegakaryocytes contained poorly developed endoplasmic reticulum with rare polysomes. In summary, Gata1lowmice are a bona fide model of MF, which recapitulates the hyperactivation of the TPO/MPL/JAK2 axis observed in megakaryocytes from myelofibrotic patients.

AB - Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1lowmutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1lowmice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1lowLSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice. Gata1lowmarrow and spleen contained more JAK2/STAT5 than wild-type tissues, an indication that these organs were reach of TPO-responsive cells. Moreover, treatment of Gata1lowmice with the JAK inhibitor ruxolitinib reduced their splenomegaly. Also in Gata1lowmice activation of the TPO/MPL axis was associated with a RSP14 deficiency and a discordant microarray ribosome signature (reduced RPS24, RPS26 and SBDS expression). Finally, electron microscopy revealed that Gata1lowmegakaryocytes contained poorly developed endoplasmic reticulum with rare polysomes. In summary, Gata1lowmice are a bona fide model of MF, which recapitulates the hyperactivation of the TPO/MPL/JAK2 axis observed in megakaryocytes from myelofibrotic patients.

KW - Animals

KW - Disease Models, Animal

KW - Female

KW - GATA1 Transcription Factor/genetics

KW - Humans

KW - Male

KW - Mice

KW - Primary Myelofibrosis/genetics

KW - Ribosomal Proteins/genetics

KW - Thrombopoietin/metabolism

U2 - 10.1038/bcj.2017.51

DO - 10.1038/bcj.2017.51

M3 - Article

C2 - 28622305

VL - 7

SP - e572

JO - Blood Cancer Journal

JF - Blood Cancer Journal

SN - 2044-5385

IS - 6

ER -