Impact of inflammation on early hematopoiesis and the microenvironment

Takizawa, Hajime; Manz, Markus G.

doi:10.1007/s12185-017-2266-5

Cited by 35 publications

(26 citation statements)

References 62 publications

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“…Of note, JAK2 mutations are uncommon in de novo AML 11 and the majority of AML cell lines. 12 Given the role of the microenvironment in regulating inflammatory processes, 13,14 we investigated the influence of stromal cells on JAK/STAT activity in human AML. Coculturing primary human AML cells with HS-5 stromal cells for 4 days induced a 1.6-fold increase in phosphorylation of STAT3, but not STAT5, in AML and importantly was not changed in nonleukemic MNCs ( Figure 1E).…”

Section: Aml Induces An Inflammatory Response In the Bone Marrow Nichmentioning

confidence: 99%

Inflammation-driven activation of JAK/STAT signaling reversibly accelerates acute myeloid leukemia in vitro

et al. 2020

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Abstract Acute myeloid leukemia (AML) is characterized by a high relapse rate and dismal long-term overall survival which is related to persistence of leukemia-initiating cells in their niche. Different animal models of myeloid malignancies reveal how neoplastic cells alter the structural and functional characteristics of the hematopoietic stem cell niche to reinforce malignancy. Understanding and disruption of the microenvironmental interactions with AML cells are a vital need. Malignant niches frequently go along with inflammatory responses, but their impact on cancerogenesis often remains unexplored. Here, we uncovered an aberrant production of inflammatory cytokines in untreated AML bone marrow that was proved to promote the proliferation of leukemia cells. This inflammatory response induced an activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in AML blasts as well as bone marrow stromal cells that also fostered leukemia proliferation. Inhibition of JAK/STAT signaling using the selective JAK1/2 inhibitor ruxolitinib resulted in significant antileukemic activity in AML in vitro which is mediated through both cell-autonomous and microenvironment-mediated mechanisms. However, in a xenograft transplantation model, monotherapy with ruxolitinib did not achieve substantial antileukemic activity, possibly suggesting a complementary function of JAK1/2 inhibition in AML.

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Section: Aml Induces An Inflammatory Response In the Bone Marrow Nichmentioning

confidence: 99%

Inflammation-driven activation of JAK/STAT signaling reversibly accelerates acute myeloid leukemia in vitro

et al. 2020

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“…The BM niche involves a complex interaction of multiple cell types including HSCs and stromal cells such as mesenchymal (MSCs) and endothelial cells (ECs) to maintain steady-state hematopoiesis. In the context of inflammation, these interactions are even more critical as MSCs and ECs can detect inflammatory cytokines and engage an “inflammatory loop”, harming healthy HSCs and modifying regular hematopoiesis [ 115 ]. This inflammatory state was shown to trigger fibrosis and angiogenesis, contributing to the pathogenesis of MPN [ 116 , 117 ].…”

Section: Inflammation Drives the Onset/progression Of Myeloid Malimentioning

confidence: 99%

The Critical Role of Inflammation in the Pathogenesis and Progression of Myeloid Malignancies

Craver

Alaoui

Scherber

et al. 2018

Cancers

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Hematopoietic stem cells (HSCs) maintain an organism’s immune system for a lifetime, and derangements in HSC proliferation and differentiation result in hematologic malignancies. Chronic inflammation plays a contributory if not causal role in HSC dysfunction. Inflammation induces HSC exhaustion, which promotes the emergence of mutant clones that may be resistant to an inflammatory microenvironment; this likely promotes the onset of a myeloid hematologic malignancy. Inflammatory cytokines are characteristically high in patients with myeloid malignancies and are linked to disease initiation, symptom burden, disease progression, and worsened prognostic survival. This review will cover our current understanding of the role of inflammation in the initiation, progression, and complications of myeloid hematologic malignancies, drawing from clinical studies as well as murine models. We will also highlight inflammation as a therapeutic target in hematologic malignancies.

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“…While many of these mutations are commonly seen in MDS or AML, and their presence in hematopoietic cells is associated with an increased risk of developing hematologic malignancies, the majority of these patients (99–99.5%) will never progress to frank MDS or AML ( 6 , 7 ). Since aging has been associated with a chronic inflammatory state, it is possible that clonal hematopoiesis is also promoted by inflammation ( 5 , 8 , 9 ). This could occur through increased genomic instability, which can lead to the acquisition of mutations, followed by the positive selection of mutant clones.…”

Section: Clonal Hematopoiesis Mutations In Epigenetic Modifiers Andmentioning

confidence: 99%

“…Inflammatory signaling can occur both in hematopoietic cells and in the hematopoietic niche, significantly altering the crosstalk between hematopoietic cells and their microenvironment [reviewed in Ref. ( 5 )]. Interestingly, some of the same inflammatory pathways may actually promote the differentiation and loss of self-renewal of LSCs in AML.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

2017

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Hematopoietic stem cells (HSCs) are a rare subset of bone marrow cells that usually exist in a quiescent state, only entering the cell cycle to replenish the blood compartment, thereby limiting the potential for errors in replication. Inflammatory signals that are released in response to environmental stressors, such as infection, trigger active cycling of HSCs. These inflammatory signals can also directly induce HSCs to release cytokines into the bone marrow environment, promoting myeloid differentiation. After stress myelopoiesis is triggered, HSCs require intracellular signaling programs to deactivate this response and return to steady state. Prolonged or excessive exposure to inflammatory cytokines, such as in prolonged infection or in chronic rheumatologic conditions, can lead to continued HSC cycling and eventual HSC loss. This promotes bone marrow failure, and can precipitate preleukemic states or leukemia through the acquisition of genetic and epigenetic changes in HSCs. This can occur through the initiation of clonal hematopoiesis, followed by the emergence preleukemic stem cells (pre-LSCs). In this review, we describe the roles of multiple inflammatory signaling pathways in the generation of pre-LSCs and in progression to myelodysplastic syndrome (MDS), myeloproliferative neoplasms, and acute myeloid leukemia (AML). In AML, activation of some inflammatory signaling pathways can promote the cycling and differentiation of LSCs, and this can be exploited therapeutically. We also discuss the therapeutic potential of modulating inflammatory signaling for the treatment of myeloid malignancies.

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Impact of inflammation on early hematopoiesis and the microenvironment

Cited by 35 publications

References 62 publications

Inflammation-driven activation of JAK/STAT signaling reversibly accelerates acute myeloid leukemia in vitro

Inflammation-driven activation of JAK/STAT signaling reversibly accelerates acute myeloid leukemia in vitro

The Critical Role of Inflammation in the Pathogenesis and Progression of Myeloid Malignancies

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

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