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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

Proposal of a natural history of hematopoietic and stromal cell interactions in bone marrow from PMF patients. The highly inflammed bone marrow environment in PMF is compared to being hit by a “storm” of cytokines [12] (0). (1) This inflammatory environment could involve hematopoietic stem cells (HSCs) and/or mesenchymal stromal cells (MSCs). (2) Clonal events (that would be favored/driven by inflammation (?) [13]) would give rise to clonal hematopoietic cell(s) which will further differentiate into megakaryocytes and monocytes and produce large amount of inflammatory cytokines. (3) These cytokines would modify the bone marrow microenvironment, leading (4) to a permanent impairment of MSCs and a deterioration of the hematopoietic niche. (5) Impaired MSCs would influence malignant hematopoietic cells in an altered crosstalk and over time, MSCs would become inflammatory imprinted. (5) As a result of treatment, the number of malignant hematopoietic cells will reduce. However, the influence of inflammatory imprinted MSCs that would have acquired inherited impaired functions will continue. Unless treated, disease MSCs may continue interacting with HSC and contribute to relapse of the disease (6).
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Related In: Results  -  Collection


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fig4: Proposal of a natural history of hematopoietic and stromal cell interactions in bone marrow from PMF patients. The highly inflammed bone marrow environment in PMF is compared to being hit by a “storm” of cytokines [12] (0). (1) This inflammatory environment could involve hematopoietic stem cells (HSCs) and/or mesenchymal stromal cells (MSCs). (2) Clonal events (that would be favored/driven by inflammation (?) [13]) would give rise to clonal hematopoietic cell(s) which will further differentiate into megakaryocytes and monocytes and produce large amount of inflammatory cytokines. (3) These cytokines would modify the bone marrow microenvironment, leading (4) to a permanent impairment of MSCs and a deterioration of the hematopoietic niche. (5) Impaired MSCs would influence malignant hematopoietic cells in an altered crosstalk and over time, MSCs would become inflammatory imprinted. (5) As a result of treatment, the number of malignant hematopoietic cells will reduce. However, the influence of inflammatory imprinted MSCs that would have acquired inherited impaired functions will continue. Unless treated, disease MSCs may continue interacting with HSC and contribute to relapse of the disease (6).

Mentions: In conclusion, as elegantly proposed by Hasselbalch [64, 131], chronic inflammation may be both an initiator and a driver of clonal evolution in patients with MPNs. In PMF, we suggested that once activated, the stroma is progressively inflammatory-imprinted by clonal hematopoietic cells to an “autonomous” state where it becomes independent of hematopoietic cell stimulation. Therefore, at advanced stage of the disease, this inflammatory vicious circle will become difficult/impossible to break without combined stroma targeted therapies (Figure 4).


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)

Proposal of a natural history of hematopoietic and stromal cell interactions in bone marrow from PMF patients. The highly inflammed bone marrow environment in PMF is compared to being hit by a “storm” of cytokines [12] (0). (1) This inflammatory environment could involve hematopoietic stem cells (HSCs) and/or mesenchymal stromal cells (MSCs). (2) Clonal events (that would be favored/driven by inflammation (?) [13]) would give rise to clonal hematopoietic cell(s) which will further differentiate into megakaryocytes and monocytes and produce large amount of inflammatory cytokines. (3) These cytokines would modify the bone marrow microenvironment, leading (4) to a permanent impairment of MSCs and a deterioration of the hematopoietic niche. (5) Impaired MSCs would influence malignant hematopoietic cells in an altered crosstalk and over time, MSCs would become inflammatory imprinted. (5) As a result of treatment, the number of malignant hematopoietic cells will reduce. However, the influence of inflammatory imprinted MSCs that would have acquired inherited impaired functions will continue. Unless treated, disease MSCs may continue interacting with HSC and contribute to relapse of the disease (6).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4660030&req=5

fig4: Proposal of a natural history of hematopoietic and stromal cell interactions in bone marrow from PMF patients. The highly inflammed bone marrow environment in PMF is compared to being hit by a “storm” of cytokines [12] (0). (1) This inflammatory environment could involve hematopoietic stem cells (HSCs) and/or mesenchymal stromal cells (MSCs). (2) Clonal events (that would be favored/driven by inflammation (?) [13]) would give rise to clonal hematopoietic cell(s) which will further differentiate into megakaryocytes and monocytes and produce large amount of inflammatory cytokines. (3) These cytokines would modify the bone marrow microenvironment, leading (4) to a permanent impairment of MSCs and a deterioration of the hematopoietic niche. (5) Impaired MSCs would influence malignant hematopoietic cells in an altered crosstalk and over time, MSCs would become inflammatory imprinted. (5) As a result of treatment, the number of malignant hematopoietic cells will reduce. However, the influence of inflammatory imprinted MSCs that would have acquired inherited impaired functions will continue. Unless treated, disease MSCs may continue interacting with HSC and contribute to relapse of the disease (6).
Mentions: In conclusion, as elegantly proposed by Hasselbalch [64, 131], chronic inflammation may be both an initiator and a driver of clonal evolution in patients with MPNs. In PMF, we suggested that once activated, the stroma is progressively inflammatory-imprinted by clonal hematopoietic cells to an “autonomous” state where it becomes independent of hematopoietic cell stimulation. Therefore, at advanced stage of the disease, this inflammatory vicious circle will become difficult/impossible to break without combined stroma targeted therapies (Figure 4).

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