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

Le Bousse-Kerdilès 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

Role of growth factors in PMF stromal reaction. In PMF, myelofibrosis is a multifactor process resulting from alterations of fibroblasts/MSC leading to an increased deposit of extracellular matrix components resulting from growth factors released by malignant hematopoietic cells and especially MK and monocytes. These growth factors would further activate stromal cells, leading to myelofibrosis, osteosclerosis and neoangiogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3368798&req=5

Figure 3: Role of growth factors in PMF stromal reaction. In PMF, myelofibrosis is a multifactor process resulting from alterations of fibroblasts/MSC leading to an increased deposit of extracellular matrix components resulting from growth factors released by malignant hematopoietic cells and especially MK and monocytes. These growth factors would further activate stromal cells, leading to myelofibrosis, osteosclerosis and neoangiogenesis.

Mentions: It is accepted that myelofibrosis associating the clonal myeloproliferation is a multifactor process resulting from alterations of fibroblasts leading to the modified expression of adhesion molecules and to an increased deposit of extracellular matrix components [30]. This accumulation is suggested to be the consequence of intramedullary release of growth factors by the malignant hematopoietic clone and especially by dysplastic megakaryocytes [31]. Among these growth factors, some would further activate mesenchymal cells (PDGF, bFGF, TGFβ...), leading to the myelofibrosis, as well as endothelial cells (bFGF, VEGF, IL-8...), participating in the neoangiogenesis [32] (Figure 3). It has been hypothesized that an increased production of osteoprotegerin by stromal and endothelial cells contributed to the unbalanced osteoblast production leading to the osteosclerosis frequently associated with myelofibrosis and to vascular complications [33]. The abnormal trafficking of CD34+ hematopoietic progenitors and endothelial precursors that features PMF is likely resulting from modification of their adherence to the bone marrow stroma allowing them to escape from this niche into the circulation with homing to the spleen and liver. Several mechanisms, including disturbance of CXCL12/SDF-1α-CXCR4 signal [34] through a hypermethylation of its CXCR4 receptor resulting in a down-regulation of its expression [35], and an increased extracellular matrix proteolytic activity [36], also participate in this migration. Thus, in PMF, whereas the primitive molecular event is still unknown, the "specificity" of the pathological process would result from alterations in the cross talk between hematopoietic and stromal cells. In this process, stromal cells are conditioned by growth factor produced by malignant hematopoietic cells and reciprocally, by acquiring new properties, stromal cells create a pathological microenvironment that takes part in the development and maintenance of the clone, leading to an imbalance that compromises normal hematopoiesis (Figure 4). Therefore, ignoring the environmental cues that control HSC fate during homeostasis, neoplastic HSCs can survive at anatomical sites (i.e., spleen and liver) unable to support normal adult hematopoiesis [8].


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

Le Bousse-Kerdilès MC - Fibrogenesis Tissue Repair (2012)

Role of growth factors in PMF stromal reaction. In PMF, myelofibrosis is a multifactor process resulting from alterations of fibroblasts/MSC leading to an increased deposit of extracellular matrix components resulting from growth factors released by malignant hematopoietic cells and especially MK and monocytes. These growth factors would further activate stromal cells, leading to myelofibrosis, osteosclerosis and neoangiogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Role of growth factors in PMF stromal reaction. In PMF, myelofibrosis is a multifactor process resulting from alterations of fibroblasts/MSC leading to an increased deposit of extracellular matrix components resulting from growth factors released by malignant hematopoietic cells and especially MK and monocytes. These growth factors would further activate stromal cells, leading to myelofibrosis, osteosclerosis and neoangiogenesis.
Mentions: It is accepted that myelofibrosis associating the clonal myeloproliferation is a multifactor process resulting from alterations of fibroblasts leading to the modified expression of adhesion molecules and to an increased deposit of extracellular matrix components [30]. This accumulation is suggested to be the consequence of intramedullary release of growth factors by the malignant hematopoietic clone and especially by dysplastic megakaryocytes [31]. Among these growth factors, some would further activate mesenchymal cells (PDGF, bFGF, TGFβ...), leading to the myelofibrosis, as well as endothelial cells (bFGF, VEGF, IL-8...), participating in the neoangiogenesis [32] (Figure 3). It has been hypothesized that an increased production of osteoprotegerin by stromal and endothelial cells contributed to the unbalanced osteoblast production leading to the osteosclerosis frequently associated with myelofibrosis and to vascular complications [33]. The abnormal trafficking of CD34+ hematopoietic progenitors and endothelial precursors that features PMF is likely resulting from modification of their adherence to the bone marrow stroma allowing them to escape from this niche into the circulation with homing to the spleen and liver. Several mechanisms, including disturbance of CXCL12/SDF-1α-CXCR4 signal [34] through a hypermethylation of its CXCR4 receptor resulting in a down-regulation of its expression [35], and an increased extracellular matrix proteolytic activity [36], also participate in this migration. Thus, in PMF, whereas the primitive molecular event is still unknown, the "specificity" of the pathological process would result from alterations in the cross talk between hematopoietic and stromal cells. In this process, stromal cells are conditioned by growth factor produced by malignant hematopoietic cells and reciprocally, by acquiring new properties, stromal cells create a pathological microenvironment that takes part in the development and maintenance of the clone, leading to an imbalance that compromises normal hematopoiesis (Figure 4). Therefore, ignoring the environmental cues that control HSC fate during homeostasis, neoplastic HSCs can survive at anatomical sites (i.e., spleen and liver) unable to support normal adult hematopoiesis [8].

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