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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

Pathophysiological characteristics of PMF. Primary myelofibrosis is characterized by a clonal amplification of hematopoietic stem cells (HSCs) and a prominent proliferation of "dystrophic" megakaryocytes (MK) that partly result from the presence of gain-of-function mutations involving JAK2 and MPL genes and that is associated with a migration of HSC from bone marrow (BM) to spleen and liver through peripheral blood (PB). Such myeloproliferation is associated with alterations of stroma featured by a myelofibrosis, an osteosclerosis and a neoangiogenesis. This stromal reaction is reported to be secondary to the stimulation of stromal cells including fibroblasts, osteoblasts and endothelial cells by growth factors (GFs) produced in excess by cells from the hematopoietic clone and especially by MK cells.
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Figure 1: Pathophysiological characteristics of PMF. Primary myelofibrosis is characterized by a clonal amplification of hematopoietic stem cells (HSCs) and a prominent proliferation of "dystrophic" megakaryocytes (MK) that partly result from the presence of gain-of-function mutations involving JAK2 and MPL genes and that is associated with a migration of HSC from bone marrow (BM) to spleen and liver through peripheral blood (PB). Such myeloproliferation is associated with alterations of stroma featured by a myelofibrosis, an osteosclerosis and a neoangiogenesis. This stromal reaction is reported to be secondary to the stimulation of stromal cells including fibroblasts, osteoblasts and endothelial cells by growth factors (GFs) produced in excess by cells from the hematopoietic clone and especially by MK cells.

Mentions: Besides the potential role of altered growth factor signaling pathways, a number of converging arguments suggests that changes within the hematopoietic environment also take part in MPN pathogenesis. The most significant elements in favor of this assumption emerge from studies on PMF that is the rarest and most complex Ph- MPN. Primary myelofibrosis is characterized by an extramedullary hematopoiesis with progressive hepato-splenomegaly resulting from the prominent mobilization of hematopoietic progenitors from bone marrow to spleen and liver. Such alteration of hematopoiesis is constantly associated with profound modifications of the bone marrow and spleen stroma as demonstrated by the presence of myelofibrosis, osteosclerosis and neoangiogenesis in PMF patients [5] (Figure 1).


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

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

Pathophysiological characteristics of PMF. Primary myelofibrosis is characterized by a clonal amplification of hematopoietic stem cells (HSCs) and a prominent proliferation of "dystrophic" megakaryocytes (MK) that partly result from the presence of gain-of-function mutations involving JAK2 and MPL genes and that is associated with a migration of HSC from bone marrow (BM) to spleen and liver through peripheral blood (PB). Such myeloproliferation is associated with alterations of stroma featured by a myelofibrosis, an osteosclerosis and a neoangiogenesis. This stromal reaction is reported to be secondary to the stimulation of stromal cells including fibroblasts, osteoblasts and endothelial cells by growth factors (GFs) produced in excess by cells from the hematopoietic clone and especially by MK cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Pathophysiological characteristics of PMF. Primary myelofibrosis is characterized by a clonal amplification of hematopoietic stem cells (HSCs) and a prominent proliferation of "dystrophic" megakaryocytes (MK) that partly result from the presence of gain-of-function mutations involving JAK2 and MPL genes and that is associated with a migration of HSC from bone marrow (BM) to spleen and liver through peripheral blood (PB). Such myeloproliferation is associated with alterations of stroma featured by a myelofibrosis, an osteosclerosis and a neoangiogenesis. This stromal reaction is reported to be secondary to the stimulation of stromal cells including fibroblasts, osteoblasts and endothelial cells by growth factors (GFs) produced in excess by cells from the hematopoietic clone and especially by MK cells.
Mentions: Besides the potential role of altered growth factor signaling pathways, a number of converging arguments suggests that changes within the hematopoietic environment also take part in MPN pathogenesis. The most significant elements in favor of this assumption emerge from studies on PMF that is the rarest and most complex Ph- MPN. Primary myelofibrosis is characterized by an extramedullary hematopoiesis with progressive hepato-splenomegaly resulting from the prominent mobilization of hematopoietic progenitors from bone marrow to spleen and liver. Such alteration of hematopoiesis is constantly associated with profound modifications of the bone marrow and spleen stroma as demonstrated by the presence of myelofibrosis, osteosclerosis and neoangiogenesis in PMF patients [5] (Figure 1).

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