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Primary myelofibrosis and the "bad seeds in bad soil" concept.

Le Bousse-Kerdil├Ęs MC - Fibrogenesis Tissue Repair (2012)

Bottom Line: We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells.These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions.A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.

View Article: PubMed Central - HTML - PubMed

Affiliation: The French INSERM and the European EUMNET networks on Myelofibrosis, The French Intergroup of Myeloproliferative disorders (FIM), INSERM U972, Paris XI University, Laboratory of Hematology, Paul Brousse Hospital, 14, av. Paul-Vaillant Couturier ; 948007, Villejuif Cedex, France.

ABSTRACT
Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2(Val617F) mutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.

No MeSH data available.


Related in: MedlinePlus

PMF stem cells moving from niches to niches. In response to several environmental factors, an imbalance between endosteal and vascular niches within the bone marrow would favor the proliferation and mobilization of pathological stem cells from the bone marrow to the blood. These stem cells would migrate into the spleen/liver where newly created or reinitialized vascular niches would favor their homing and differentiation resulting in an extramedullary hematopoiesis in these organs.
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Figure 5: PMF stem cells moving from niches to niches. In response to several environmental factors, an imbalance between endosteal and vascular niches within the bone marrow would favor the proliferation and mobilization of pathological stem cells from the bone marrow to the blood. These stem cells would migrate into the spleen/liver where newly created or reinitialized vascular niches would favor their homing and differentiation resulting in an extramedullary hematopoiesis in these organs.

Mentions: In PMF, it could be suggested that in response to several environmental factors including cytokines, chemokines, proteases, adhesion molecules, alteration of calcium and oxygen concentration... there is an imbalance between endosteal and vascular niches within the bone marrow. Such disequilibrium would favor the proliferation and mobilization of pathological stem cells including hematopoietic, mesenchymal and endothelial stem/progenitor cells from the bone marrow to the blood, leading to bone marrow aplasia and stem cell mobilization. These stem cells would then migrate into the spleen where newly created or reinitialized vascular niches would favor their homing and abnormal differentiation resulting in an extramedullary hematopoiesis at the origin of the splenomegaly that features this disease [8] (Figure 5). Therefore, by contributing to the hematopoietic clone development, alterations of stromal cells within hematopoietic stem cell niches are key actors of PMF pathogenesis process illustrating the "Bad Seeds in Bad Soil" concept that we proposed (Figure 4).


Primary myelofibrosis and the "bad seeds in bad soil" concept.

Le Bousse-Kerdil├Ęs MC - Fibrogenesis Tissue Repair (2012)

PMF stem cells moving from niches to niches. In response to several environmental factors, an imbalance between endosteal and vascular niches within the bone marrow would favor the proliferation and mobilization of pathological stem cells from the bone marrow to the blood. These stem cells would migrate into the spleen/liver where newly created or reinitialized vascular niches would favor their homing and differentiation resulting in an extramedullary hematopoiesis in these organs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368798&req=5

Figure 5: PMF stem cells moving from niches to niches. In response to several environmental factors, an imbalance between endosteal and vascular niches within the bone marrow would favor the proliferation and mobilization of pathological stem cells from the bone marrow to the blood. These stem cells would migrate into the spleen/liver where newly created or reinitialized vascular niches would favor their homing and differentiation resulting in an extramedullary hematopoiesis in these organs.
Mentions: In PMF, it could be suggested that in response to several environmental factors including cytokines, chemokines, proteases, adhesion molecules, alteration of calcium and oxygen concentration... there is an imbalance between endosteal and vascular niches within the bone marrow. Such disequilibrium would favor the proliferation and mobilization of pathological stem cells including hematopoietic, mesenchymal and endothelial stem/progenitor cells from the bone marrow to the blood, leading to bone marrow aplasia and stem cell mobilization. These stem cells would then migrate into the spleen where newly created or reinitialized vascular niches would favor their homing and abnormal differentiation resulting in an extramedullary hematopoiesis at the origin of the splenomegaly that features this disease [8] (Figure 5). Therefore, by contributing to the hematopoietic clone development, alterations of stromal cells within hematopoietic stem cell niches are key actors of PMF pathogenesis process illustrating the "Bad Seeds in Bad Soil" concept that we proposed (Figure 4).

Bottom Line: We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells.These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions.A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.

View Article: PubMed Central - HTML - PubMed

Affiliation: The French INSERM and the European EUMNET networks on Myelofibrosis, The French Intergroup of Myeloproliferative disorders (FIM), INSERM U972, Paris XI University, Laboratory of Hematology, Paul Brousse Hospital, 14, av. Paul-Vaillant Couturier ; 948007, Villejuif Cedex, France.

ABSTRACT
Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2(Val617F) mutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.

No MeSH data available.


Related in: MedlinePlus