The thrombopoietin/MPL axis is activated in the Gata1low mouse model of myelofibrosis and is associated with a defective RPS14 signature

• Published in: Blood cancer journal (New York) Vol. 7; no. 6; p. e572
• Main Authors: Zingariello, M, Sancillo, L, Martelli, F, Ciaffoni, F, Marra, M, Varricchio, L, Rana, R A, Zhao, C, Crispino, J D, Migliaccio, A R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-06-2017; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/100; 13/106; 13/51; 13/95; 14/1; 14/28; 14/63; 45/61; 692/308/2171; 692/699/1541; 82/29; Biomedical and Life Sciences; Biomedicine; Cancer Research; Hematology; Oncology; Original; original-article; Rodents
• ISSN: 2044-5385; 2044-5385
• DOI: 10.1038/bcj.2017.51

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
Gata1
low
mutation, which reduces the levels of
Gata1
mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model.
Gata1
low
mice contained two times more
Tpo
mRNA in liver and TPO in plasma than wild-type littermates. Furthermore,
Gata1
low
LSKs 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.
Gata1
low
marrow and spleen contained more JAK2/STAT5 than wild-type tissues, an indication that these organs were reach of TPO-responsive cells. Moreover, treatment of
Gata1
low
mice with the JAK inhibitor ruxolitinib reduced their splenomegaly. Also in
Gata1
low
mice 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
Gata1
low
megakaryocytes contained poorly developed endoplasmic reticulum with rare polysomes. In summary,
Gata1
low
mice are a bona fide model of MF, which recapitulates the hyperactivation of the TPO/MPL/JAK2 axis observed in megakaryocytes from myelofibrotic patients.