scholarly journals Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis

2015 ◽  
Vol 54 (3) ◽  
pp. 234-241 ◽  
Author(s):  
Fiorella Ciaffoni ◽  
Elena Cassella ◽  
Lilian Varricchio ◽  
Margherita Massa ◽  
Giovanni Barosi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Primary Myelofibrosis ◽  
Bone Marrow Fibrosis ◽  
Autoimmune Mechanism ◽  
Tgf Β1 ◽  
Marrow Fibrosis

scholarly journals Neoplastic fibrocytes play an essential role in bone marrow fibrosis in Jak2V617F-induced primary myelofibrosis mice

Leukemia ◽  
2020 ◽  
Author(s):  
Yoshinori Ozono ◽  
Kotaro Shide ◽  
Takuro Kameda ◽  
Ayako Kamiunten ◽  
Yuki Tahira ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Role ◽  
Primary Myelofibrosis ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis

Is Thalidomide the Sole Treatment of Primary Myelofibrosis? Report of a Case with Complete Reversal of Bone Marrow Fibrosis and Splenomegaly.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4905-4905
Author(s):  
Alain Berrebi ◽  
Lev Shvidel ◽  
Irena Shpivak ◽  
Edit Feldberg
Keyword(s):  
Bone Marrow ◽  
Folic Acid ◽  
Bone Marrow Biopsy ◽  
Low Dose ◽  
Oral Prednisone ◽  
Young Patients ◽  
Primary Myelofibrosis ◽  
Bone Marrow Fibrosis ◽  
Complete Reversal ◽  
Marrow Fibrosis

Abstract Primary myelofibrosis (MF) is a chronic progressive disorder incurable except for allo-transplantation in young patients. Thalidomide which down-regulates cytokine release involved in fibrosis (VEGF, TGF-beta, beta-FGF, PDGF) and angiogenesis has been used with variable responses in the treatment of MF. We report a patient who achieved a complete response of MF after being treated with low doses thalidomide. An 82-year-old patient, with no other medical problems, was followed since 1993 because of erythrocytosis and mild splenomegaly, his bone marrow biopsy revealed tree-lineage hyperplasia and moderate fibrosis. The patient was initially treated with phlebotomy when needed, and afterwards by a low dose of hydroxyurea. Five years later, when anemia developed (Hb<10 g/dl) together with prominent splenomegaly (18 cm) and aggravation of bone marrow fibrosis, combination treatment with androgen, vitamin B complex and folic acid was started. Since 2003 the patient became transfusion dependent (2 packed red cells every 3 weeks). He had a huge splenomegaly (up to the pubis), Hb 8.3 g/dl, WBC 4×109/l with occasionally blasts, platelet count 75×109/l, and LDH 1220 U. Bone marrow biopsy revealed severe reticulin and collagen fibrosis with no hematopoiesis. In view of the progressive painful splenomegaly and deep pancytopenia, splenectomy was advised which was refused by the patient. Therefore alternative treatment with thalidomide was considered and started at a dose of 50 mg/day together with 5 mg/day prednisone in March, 2004. B-complex and folic acid were continued. Four months later, the blood transfusion requirement decreased, and gradually was abolished. The spleen size started to be smaller and became impalpable. Currently after 30 months of treatment blood count showed Hb 12.0 g/dl, WBC 2.6×109//l, Plt 140×109/l. The repeated bone biopsy showed a dramatic change with complete normalization of hematopoiesis and total resolution of collagen. The blood film doesn’t disclose any tear drops. Thalidomide monotherapy in moderate and high doses (200–800 mg/day) produces a 20–50% response rate in MF-associated anemia and thrombocytopenia, has mild impact on splenomegaly, but is poorly tolerated. Most patients are withdrawn from treatment because of adverse effects in first three months. Mesa et al (Blood, 2003) improved tolerability and efficacy of therapy using thalidomide in low dose 50 mg/day along with a three months oral prednisone. An objective clinical response was demonstrated in 62% patients; however, complete reversal of fibrosis has never been mentioned before. In conclusion, we report a patient with a very advanced MF who showed complete hematological response to low dose thalidomide with complete reversal of bone marrow fibrosis and splenomegaly. We suggest that this exceptional response might be due to the long continuous tolerable low dose treatment (30 months) and a combination with prednisone, B-complex vitamins and folic acid.

Contribution of comorbidities and grade of bone marrow fibrosis to the prognosis of survival in patients with primary myelofibrosis

2014 ◽  
Vol 31 (3) ◽  
Author(s):  
Danijela Lekovic ◽  
Mirjana Gotic ◽  
Maja Perunicic-Jovanovic ◽  
Ana Vidovic ◽  
Andrija Bogdanovic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Primary Myelofibrosis ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis

Proteasome Inhibitor Bortezomib Can Inhibit Bone Marrow Fibrosis Development in a Murine Model of Myelofibrosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2582-2582 ◽  
Author(s):  
Orianne Wagner-Ballon ◽  
Thomas Gastinne ◽  
Micheline Tulliez ◽  
Catherine Lacout ◽  
Didier Pisani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Proteasome Inhibitor ◽  
Transforming Growth Factor ◽  
Mice Model ◽  
Bone Marrow Fibrosis ◽  
Bortezomib Treatment ◽  
Pathway Activation ◽  
Tgf Β1 ◽  
Marrow Fibrosis

Abstract Several lines of evidence obtained from idiopathic myelofibrosis (IM) studies are in favour of a crucial role of the NF-κB pathway activation in myelofibrosis induction. It has been demonstrated that megakaryocytes, monocytes but also CD34+ cells from IM patients present a spontaneous NF-κB pathway activation associated with transforming growth factor-β1 (TGF-β1) secretion. This growth factor has been previously shown as the main fibrogenic cytokine involved in the myelofibrosis development. Mice exposed to high systemic levels of thrombopoietin (TPO) mediated by a retroviral vector (TPOhigh mice) develop a myeloproliferative disorder featuring numerous aspects of the human disease including bone marrow fibrosis, extramedullary hematopoiesis and dysmegakaryopoiesis. Moreover, TPOhigh mice display high plasma levels of IL-1α suggesting that the NF-κB pathway may play a role in this model of fibrosis. We then conducted a study to investigate whether NF-κB inhibition in this mice model could have an impact on myelofibrosis development using the proteasome inhibitor bortezomib. One month after engraftment with TPO-overexpressing hematopoietic cells, 2 groups of 20 immunocompetent C57BL/6J mice displaying similar myeloproliferation induced by TPO overexpression were constituted. Mice engrafted were treated twice a week, with either bortezomib (1 mg/kg) or a placebo for 4 weeks. At the end of this protocol, mice from both groups were examined for histological and haematological analysis including TGF-β1 and IL-1α levels determination. Here, we demonstrate that: i) the NF-κB pathway is activated in TPOhigh spleen cells and bortezomib treatment is able to inhibit this activation; ii) bortezomib treatment is able to decrease plasma concentration of TGF-β1 and IL-1α in mice as well as TGF-β1 content in extracellular fluids of marrow and spleen; iii) myelofibrosis development is inhibited after bortezomib treatment. These results emphasize the interest of developing bortezomib treatment in IM patients.

scholarly journals The European Consensus on grading of bone marrow fibrosis allows a better prognostication of patients with primary myelofibrosis

2012 ◽  
Vol 25 (9) ◽  
pp. 1193-1202 ◽  
Author(s):  
Umberto Gianelli ◽  
Claudia Vener ◽  
Anna Bossi ◽  
Ivan Cortinovis ◽  
Alessandra Iurlo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Primary Myelofibrosis ◽  
Bone Marrow Fibrosis ◽  
European Consensus ◽  
Marrow Fibrosis

scholarly journals Abstract 2046: Egr-1 promotes bone marrow fibrosis in primary myelofibrosis

2019 ◽  
Author(s):  
Rekha M. Rao ◽  
Amar Kumar ◽  
Pratikkumar Vekaria ◽  
Abdulraheem Yacoub ◽  
Barry Skikne ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Primary Myelofibrosis ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis

Quantitative Analysis of Growth Factor Production in the Mechanism of Fibrosis in Agnogenic Myeloid Metaplasia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4272-4272
Author(s):  
Jen-Chin Wang ◽  
Tsong S. Chang ◽  
Amit Goldberg ◽  
Allan D. Novetsky ◽  
Jeffrey Lipton
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Quantitative Analysis ◽  
Growth Factor ◽  
Bone Marrow Fibrosis ◽  
Myeloid Metaplasia ◽  
Agnogenic Myeloid Metaplasia ◽  
Growth Factor Production ◽  
Tgf Β1 ◽  
Marrow Fibrosis

Abstract There are previous reports that growth factors including TGF-β1, PDGF and FGF produced by megakaryocytes are responsible for the etiology of fibrosis in agnogenic myeloid metaplasia (AMM). Due to the technical difficulty in isolating enough megakaryocytes from the inaspirable bone marrow from patients with AMM, a quantitative analysis of these growth factors produced by the megakaryocytes and correlated to the degree of myelofibrosis has not been able to be performed. The present study employed the cell culture technique to grow megakaryocytes from blood CD 34+ cells and then perform the quantitative analysis of these growth factors, compared with other sources such as monocyte-macrophage lineages and correlated to the degree of bone marrow fibrosis. We found TGF-β1, PDGF and FGF produced by the megakaryocytes were significantly elevated in AMM compared with normal controls (p<0.05) and TGF-β1 was more abundantly produced than PDGF or FGF. While these growth factors are several fold elevated in AMM compared with other MPD including essential thrombocythemia (ET), polycythemia vera (PV), it was not statistically significant. A quantitative analysis of these growth factors produced by the CD 14+ cells in the blood and bone marrow showed that these growth factors were not significantly elevated in AMM compared with other MPD or controls and were significantly elevated only in some patients (defined as elevation of more than 2 SD of the controls). The correlation of these growth factors produced by the megakaryocytes or monocyte-macrophage lineages with degree of myelofibrosis in 12 patients with AMM were r=0.73 and 0.23 respectively (Non parametric (Spearman) correlation with two-tailed analysis was used to calculate the correlation). We concluded: In AMM, these fibrosing growth factors are mainly produced by the megakaryocytes and in some patients, monocyte-macrophage lineages may contribute to the production of these growth factor production. TGF-β1 is more abundantly produced from the megakaryocytes than PDGF or FGF confirming TGF-β1 is the most important fibrosing growth factor in the pathogenesis of myelofibrosis in AMM. A statistically significant correlation of the growth factor and degree of myelofibrosis in AMM suggests that these fibroing growth factors produced by the megakaryocytes are main etiology of bone marrow fibrosis in AMM.

scholarly journals EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis

2019 ◽  
Vol 216 (3) ◽  
pp. 587-604 ◽  
Author(s):  
Alessandro Malara ◽  
Cristian Gruppi ◽  
Vittorio Abbonante ◽  
Daniele Cattaneo ◽  
Luigi De Marco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cell ◽  
Primary Myelofibrosis ◽  
Extramedullary Hematopoiesis ◽  
Healthy Controls ◽  
Bone Marrow Fibrosis ◽  
Progenitor Cell Proliferation ◽  
And Function ◽  
Marrow Fibrosis ◽  
Pathological Situation

The fibronectin EDA isoform (EDA FN) is instrumental in fibrogenesis but, to date, its expression and function in bone marrow (BM) fibrosis have not been explored. We found that mice constitutively expressing the EDA domain (EIIIA+/+), but not EDA knockout mice, are more prone to develop BM fibrosis upon treatment with the thrombopoietin (TPO) mimetic romiplostim (TPOhigh). Mechanistically, EDA FN binds to TLR4 and sustains progenitor cell proliferation and megakaryopoiesis in a TPO-independent fashion, inducing LPS-like responses, such as NF-κB activation and release of profibrotic IL-6. Pharmacological inhibition of TLR4 or TLR4 deletion in TPOhigh mice abrogated Mk hyperplasia, BM fibrosis, IL-6 release, extramedullary hematopoiesis, and splenomegaly. Finally, developing a novel ELISA assay, we analyzed samples from patients affected by primary myelofibrosis (PMF), a well-known pathological situation caused by altered TPO signaling, and found that the EDA FN is increased in plasma and BM biopsies of PMF patients as compared with healthy controls, correlating with fibrotic phase.

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