Increased Differentiation of Dermal Mast Cells in Mice Lacking the Mpl Gene

Ghinassi, Barbara; Zingariello, Maria; Martelli, Fabrizio; Lorenzini, R; Vannucchi, Alessandro M.; Rana, Rosa Alba; Nishikawa, Mitsuo; Migliaccio, Giovanni; Mascarenhas, John; Migliaccio, Anna Rita

doi:10.1089/scd.2008.0323

Cited by 4 publications

(4 citation statements)

References 59 publications

(72 reference statements)

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“…TPO mRNA was expressed not only, as expected, 23 by the liver and kidney but also by all hematopoietic tissues (spleen, bone marrow and bone) and tissues containing TPO-responsive mast cells (ear, stomach and intestine) 24 , 25 both Gata1 low mice and wild-type littermates ( Table 1 ). In wild-type mice, the greatest levels of TPO mRNA were detected in the liver (>30-fold than any other tissue), followed by kidney and intestine.…”

Section: Resultssupporting

confidence: 71%

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

et al. 2017

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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 Gata1low mutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1low mice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1low 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. Gata1low 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 Gata1low mice with the JAK inhibitor ruxolitinib reduced their splenomegaly. Also in Gata1low 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 Gata1low megakaryocytes contained poorly developed endoplasmic reticulum with rare polysomes. In summary, Gata1low mice 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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Section: Resultssupporting

confidence: 71%

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

et al. 2017

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“…In addition to dysmyelopoiesis and loss of LSK cells half of the mice that overexpressed Mpl in our experiments had increased numbers of mast cells in the BM. Mast cell differentiation is controlled by an interplay of c-Kit and Mpl signaling and Mpl −/− mice present with reduced numbers of mast cell progenitors but an increase of mature mast cells in the BM 28,29. Thus all symptoms found in the pancytopenic phase argue for a severe systemic crisis of hematopoiesis induced by ectopic Mpl expression, leading to exhaustion of HSC and altered differentiation of progeny cells.…”

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confidence: 99%

Gene Therapy of Mpl Deficiency: Challenging Balance Between Leukemia and Pancytopenia

et al. 2010

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Signaling of the thrombopoietin (THPO) receptor MPL is critical for the maintenance of hematopoietic stem cells (HSCs) and megakaryocytic differentiation. Inherited loss-of-function mutations of MPL cause severe thrombocytopenia and aplastic anemia, a syndrome called congenital amegakaryocytic thrombocytopenia (CAMT). With the aim to assess the toxicity of retroviral expression of Mpl as a basis for further development of a gene therapy for this disorder, we expressed Mpl in a murine bone marrow transplantation (BMT) model. Treated mice developed a profound yet transient elevation of multilineage hematopoiesis, which showed morphologic features of a chronic myeloproliferative disorder (CMPD) with progressive pancytopenia. Ten percent of mice (3/27) developed erythroleukemia, associated with insertional activation of Sfpi1 and Fli1. The majority of transplanted mice developed a progressive pancytopenia with histopathological features of a myelodysplastic syndrome (MDS)-like disorder. To avoid these adverse reactions, improved retroviral vectors were designed that mediate reduced and more physiological Mpl expression. Self-inactivating gamma-retroviral vectors were constructed that expressed Mpl from the phosphoglycerate kinase (PGK) or the murine Mpl promoter. Mice that received BM cells expressing Mpl from the Mpl promoter were free of any previously observed adverse reactions.

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“…Using the Chen et al definition of bone marrow mast cell progenitors as FcεRI − , CD27 − , β7 integrin + and IL33R + , loss of Mpl resulted in decreased numbers of mast cell progenitors in the spleen and bone marrow, but increased numbers of mature mast cells based on histological staining and fluorescent staining for KIT and FcεRI. 16,52,53 There were also increased numbers of mast cells in the spleen, bone marrow, skin, stomach and peritoneal cavity, suggesting that TPO via its receptor plays an important role in controlling the number of mast cell in several different sites.…”

Section: Basal Homing Of Mast Cell Progenitors (Fig 1)mentioning

confidence: 99%

Mast Cell Progenitor Trafficking and Maturation

Hallgren

Gurish

2011

Advances in Experimental Medicine and Biology

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Mast cells are derived from the hematopoietic progenitors found in bone marrow and spleen. Committed mast cell progenitors are rare in bone marrow suggesting they are rapidly released into the blood where they circulate and move out into the peripheral tissues. This migration is controlled in a tissue specific manner. Basal trafficking to the intestine requires expression of α4β7 integrin and the chemokine receptor CXCR2 by the mast cell progenitors and expression of MAdCAM-1 and VCAM-1 in the intestinal endothelium; and is also controlled by dendritic cells expressing the transcriptional regulatory protein T-bet. None of these play a role in basal trafficking to the lung. With the induction of allergic inflammation in the lung, there is marked recruitment of committed mast cell progenitors to lung and these cells must express α4β7 and α4β1 integrins. Within the lung there is a requirement for expression of VCAM-1 on the endothelium that is regulated by CXCR2, also expressed on the endothelium. There is a further requirement for expression of the CCR2/CCL2 pathways for full recruitment of the mast cell progenitors to the antigen-inflamed lung.

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Increased Differentiation of Dermal Mast Cells in Mice Lacking the Mpl Gene

Cited by 4 publications

References 59 publications

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

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

Gene Therapy of Mpl Deficiency: Challenging Balance Between Leukemia and Pancytopenia

Mast Cell Progenitor Trafficking and Maturation

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