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 language | English |
|---|---|
| Pages (from-to) | e572 |
| Journal | Blood Cancer Journal |
| Volume | 7 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 16 2017 |
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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 journal › Article
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TY - JOUR
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 -