FLT3-Mediated p38–MAPK Activation Participates in the Control of Megakaryopoiesis in Primary Myelofibrosis

Desterke, Christophe; Bilhou-Nabéra, Chrystèle; Guerton, Bernadette; Martinaud, Christophe; Tonetti, Carole; Clay, Denis; Guglielmelli, Paola; Vannucchi, Alessandro M.; Bron, Dominique; Hasselbalch, Hans Carl; Dupriez, Brigitte; Benzoubir, Nassima; Bourgeade, Marie‐Françoise; Pierre-Louis, Olivier; Lazar, Vladimir; Vainchenker, William; Bennaceur-Griscelli, Annelise; Gisslinger, Heinz; Giraudier, Stéphane; Bousse‐Kerdilès, Marie‐Caroline Le

doi:10.1158/0008-5472.can-10-1731

Cited by 45 publications

(34 citation statements)

References 48 publications

(43 reference statements)

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“…Over-expression of EVI1 in mice enhances megakaryocyte proliferation and in humans is associated with hematopoietic disorders characterized by dysmegakaryopoiesis 22 . Therefore, over-expression of EVI1 is also consistent with the increased megakaryopoiesis observed in BM of PMF patients and suggests that EVI1 may be the element downstream of the activated p38-MAPK signaling that controls megakaryopoiesis in primary myelofibrosis 25 . Increased G1 arrest and apoptosis in BM are also predicted by alterations observed in genes controlling cell cycle or involved in CML (Table 2).…”

Section: Resultssupporting

confidence: 64%

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

Ciaffoni

Cassella

Varricchio

et al. 2015

Blood Cells, Molecules, and Diseases

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Primary myelofibrosis (PMF) is characterized by megakaryocyte hyperplasia, dysplasia and death with progressive reticulin/collagen fibrosis in marrow and hematopoiesis in extramedullary sites. The mechanism of fibrosis was investigated by comparing TGF-β1 signaling of marrow and spleen of patients with PMF and of non-diseased individuals. Expression of 39 (23 up-regulated and 16 down-regulated) and 38 (8 up-regulated and 30 down-regulated) TGF-β1 signaling genes was altered in marrow and spleen of PMF patients, respectively. Abnormalities included genes of TGF-β1 signaling, cell cycling and abnormal in chronic myeloid leukemia (EVI1 and p21CIP) (both marrow and spleen) and Hedgehog (marrow only) and p53 (spleen only) signaling. Pathway analyses of these alterations predict increased osteoblast differentiation, ineffective hematopoiesis and fibrosis driven by non-canonical TGF-β1 signaling in marrow and increased proliferation and defective DNA repair in spleen. Since activation of non-canonical TGF-β1 signaling is associated with fibrosis in autoimmune diseases, the hypothesis that fibrosis in PMF results from an autoimmune process triggered by dead megakaryocytes was tested by determining that PMF patients expressed plasma levels of mitochondrial DNA and anti-mitochondrial antibodies greater than normal controls. These data identify autoimmunity as a possible cause of marrow fibrosis in PMF.

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Section: Resultssupporting

confidence: 64%

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

Ciaffoni

Cassella

Varricchio

et al. 2015

Blood Cells, Molecules, and Diseases

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“…As expected, MNCs from JAK2 + -PV expressed greater than normal levels of p38 and pp38 (downstream targets of JAK2 known to be activated in MPNs [40]), which were analyzed as a control. JAK2 + -PV also expressed levels of N-CALR greater than normal but had levels of C-CALR similar to those expressed by NS (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Calreticulin control of human stress erythropoiesis is impaired by JAK2V617F in polycythemia vera

Falchi

Varricchio

Martelli

et al. 2017

Experimental Hematology

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Calreticulin (CALR) is a Ca2+-binding protein that shuttles among cellular compartments with proteins bound to its N/P domains. The knowledge that activation of the human erythropoietin receptor induces Ca2+ fluxes prompted us to investigate the role of CALR in human erythropoiesis. As shown by Western blot analysis, erythroblasts generated in vitro from normal sources and JAK2V617F polycythemia vera (PV) patients expressed robust levels of CALR. However, Ca2+ regulated CALR conformation only in normal cells. Normal erythroblasts expressed mostly the N-terminal domain of CALR (N-CALR) on their cell surface (as shown by flow cytometry) and C-terminal domain (C-CALR) in their cytoplasm (as shown by confocal microscopy) and expression of both epitopes decreased with maturation. In the proerythroblast (proEry) cytoplasm, C-CALR was associated with the glucocorticoid receptor (GR), which initiated the stress response. In these cells, Ca2+ deprivation and inhibition of nuclear export increased GR nuclear localization while decreasing cytoplasmic detection of C-CALR and C-CALR/GR association and proliferation in response to the GR agonist dexamethasone (Dex). C-CALR/GR association and Dex responsiveness were instead increased by Ca2+ and erythropoietin. In contrast, JAK2V617F proErys expressed normal cell-surface levels of N-CALR but barely detectable cytoplasmic levels of C-CALR. These cells contained GR mainly in the nucleus and were Dex unresponsive. Ruxolitinib rescued cytoplasmic detection of C-CALR, C-CALR/GR association, and Dex responsiveness in JAK2V617F proErys and its effects were antagonized by nuclear export and Ca2+ flux inhibitors. These results indicates that Ca2+-induced conformational changes of CALR regulate nuclear export of GR in normal erythroblasts and that JAK2V617F deregulates this function in PV.

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“…22 BM MSC were obtained from BM biopsies (PMF patients) or hip surgery (HD) by incubating BM mononuclear cells (5x10 6 /mL) for 48-72 h in plastic flasks. Adherent MSC were cultured in DMEM + 10% SVF in 5% CO 2 for three passages.…”

Section: Cd34mentioning

confidence: 99%

“…Cell lysates (10 5 cells), obtained as described previously, 22 were subjected to sodium dodecylsulfate polyacrylamide gel electrophoresis, transferred onto nitrocellulose membranes and blotted using primary monoclonal antibodies (Cell Signaling, USA). Membranes were revealed with fluorescent anti-mouse or antirabbit IgG.…”

Section: Western Blottingmentioning

confidence: 99%

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Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis

et al. 2015

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FLT3-Mediated p38–MAPK Activation Participates in the Control of Megakaryopoiesis in Primary Myelofibrosis

Cited by 45 publications

References 48 publications

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

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

The Calreticulin control of human stress erythropoiesis is impaired by JAK2V617F in polycythemia vera

Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis

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