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Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis.

Desterke C, Martinaud C, Ruzehaji N, Le Bousse-Kerdilès MC - Mediators Inflamm. (2015)

Bottom Line: The current dogma is that stromal changes are secondary to the cytokine "storm" produced by the hematopoietic clone cells.However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation.Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process.

View Article: PubMed Central - PubMed

Affiliation: Inserm UMS33, Paul Brousse Hospital, 14 Avenue Paul-Vaillant Couturier, 94800 Villejuif, France.

ABSTRACT
Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm where severity as well as treatment complexity is mainly attributed to a long lasting disease and presence of bone marrow stroma alterations as evidenced by myelofibrosis, neoangiogenesis, and osteosclerosis. While recent understanding of mutations role in hematopoietic cells provides an explanation for pathological myeloproliferation, functional involvement of stromal cells in the disease pathogenesis remains poorly understood. The current dogma is that stromal changes are secondary to the cytokine "storm" produced by the hematopoietic clone cells. However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation. Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process. In this review, we propose hypotheses suggesting that the stroma is inflammatory-imprinted by clonal hematopoietic cells up to a point where it becomes "independent" of hematopoietic cell stimulation, resulting in an inflammatory vicious circle requiring combined stroma targeted therapies.

No MeSH data available.


Related in: MedlinePlus

Data-mining prediction of inflammatory gene expression profile in BM-MSCs from PMF patients. (a) Keywords used during data-mining to link the scientific information between inflammation and altered niche in primary myelofibrosis; (b) unsupervised classification on data from inflammation prediction of gene expression profile from PMF BM-MSCs (transcriptome GSE44426); (c) functional enrichment on WikiPathway database for inflammation signature prediction of BM-MSCs from PMF patients.
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Related In: Results  -  Collection


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fig2: Data-mining prediction of inflammatory gene expression profile in BM-MSCs from PMF patients. (a) Keywords used during data-mining to link the scientific information between inflammation and altered niche in primary myelofibrosis; (b) unsupervised classification on data from inflammation prediction of gene expression profile from PMF BM-MSCs (transcriptome GSE44426); (c) functional enrichment on WikiPathway database for inflammation signature prediction of BM-MSCs from PMF patients.

Mentions: To characterize inflammation in the altered bone marrow stroma from patients, we query information from the literature by data-mining using inflammation, fibrosis, macrophage, mesenchymal stromal cells, and immunomodulation as keywords (Figure 2). A total of 253.585 connections were collected between Pubmed and gene databases (Figure 2(a)). This collected information was crossed with the gene expression profile of BM-MSCs we performed in PMF patients (GSE44426) [85] in R software [86]. The inflammatory predictive signature allows performing an unsupervised classification and identified two distinct clusters of BM-MSC samples: PMF patients and healthy donors, demonstrating that BM-MSCs from PMF patients have a typical inflammatory gene expression profile which is different from their normal counterparts (Figure 2(b)). This data-mining analysis identified several altered pathways in PMF-MSCs that would be part of the pathophysiological process. Among them, inflammatory response, oncostatin M and TGF-β signalling pathways, focal adhesion, senescence, and autophagy are the most significant within the stromal niche context (Figure 2(c)).


Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis.

Desterke C, Martinaud C, Ruzehaji N, Le Bousse-Kerdilès MC - Mediators Inflamm. (2015)

Data-mining prediction of inflammatory gene expression profile in BM-MSCs from PMF patients. (a) Keywords used during data-mining to link the scientific information between inflammation and altered niche in primary myelofibrosis; (b) unsupervised classification on data from inflammation prediction of gene expression profile from PMF BM-MSCs (transcriptome GSE44426); (c) functional enrichment on WikiPathway database for inflammation signature prediction of BM-MSCs from PMF patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4660030&req=5

fig2: Data-mining prediction of inflammatory gene expression profile in BM-MSCs from PMF patients. (a) Keywords used during data-mining to link the scientific information between inflammation and altered niche in primary myelofibrosis; (b) unsupervised classification on data from inflammation prediction of gene expression profile from PMF BM-MSCs (transcriptome GSE44426); (c) functional enrichment on WikiPathway database for inflammation signature prediction of BM-MSCs from PMF patients.
Mentions: To characterize inflammation in the altered bone marrow stroma from patients, we query information from the literature by data-mining using inflammation, fibrosis, macrophage, mesenchymal stromal cells, and immunomodulation as keywords (Figure 2). A total of 253.585 connections were collected between Pubmed and gene databases (Figure 2(a)). This collected information was crossed with the gene expression profile of BM-MSCs we performed in PMF patients (GSE44426) [85] in R software [86]. The inflammatory predictive signature allows performing an unsupervised classification and identified two distinct clusters of BM-MSC samples: PMF patients and healthy donors, demonstrating that BM-MSCs from PMF patients have a typical inflammatory gene expression profile which is different from their normal counterparts (Figure 2(b)). This data-mining analysis identified several altered pathways in PMF-MSCs that would be part of the pathophysiological process. Among them, inflammatory response, oncostatin M and TGF-β signalling pathways, focal adhesion, senescence, and autophagy are the most significant within the stromal niche context (Figure 2(c)).

Bottom Line: The current dogma is that stromal changes are secondary to the cytokine "storm" produced by the hematopoietic clone cells.However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation.Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process.

View Article: PubMed Central - PubMed

Affiliation: Inserm UMS33, Paul Brousse Hospital, 14 Avenue Paul-Vaillant Couturier, 94800 Villejuif, France.

ABSTRACT
Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm where severity as well as treatment complexity is mainly attributed to a long lasting disease and presence of bone marrow stroma alterations as evidenced by myelofibrosis, neoangiogenesis, and osteosclerosis. While recent understanding of mutations role in hematopoietic cells provides an explanation for pathological myeloproliferation, functional involvement of stromal cells in the disease pathogenesis remains poorly understood. The current dogma is that stromal changes are secondary to the cytokine "storm" produced by the hematopoietic clone cells. However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation. Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process. In this review, we propose hypotheses suggesting that the stroma is inflammatory-imprinted by clonal hematopoietic cells up to a point where it becomes "independent" of hematopoietic cell stimulation, resulting in an inflammatory vicious circle requiring combined stroma targeted therapies.

No MeSH data available.


Related in: MedlinePlus