Key Role of Inflammation in Myeloproliferative Neoplasms: Instigator of Disease Initiation, Progression. and Symptoms

Luque, Laura F. Mendez; Blackmon, Amanda; Ramanathan, Gajalakshmi; Fleischman, Angela G.

doi:10.1007/s11899-019-00508-w

Cited by 43 publications

(43 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, a high incidence of cancer, especially lymphoma, has been reported in subjects with primary immunodeficiency (20). Numerous studies have reported the association between JAK/STAT and various malignancies and inflammatory pathologies, suggesting that JAK-targeted drugs may be successful for the treatment of cancer and immune-mediated diseases (21)(22)(23)(24)(25)(26)(27). A previous study indicated that the downregulation of MYBL2 caused cell cycle arrest at the G 2 /M phase via the p53-p21-DREAM-CDE/CHR pathway (28).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of MYBL2 independently predicts a poorer prognosis in patients with clear cell renal cell carcinoma

Sun

Lin

2020

Oncol Lett

View full text Add to dashboard Cite

MYB protooncogene-like 2 (MYBL2) is a transcription factor that is upregulated and significantly associated with various human cancer types. However, the potential role of MYBL2 in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated. Therefore, the expression and biological functions of MYBL2 in ccRCC were assessed in the current study using The Cancer Genome Atlas (TCGA). A Wilcoxon signed-rank test was performed to compare MYBL2 expression between ccRCC and normal tissues. Moreover, the association between MYBL2 expression and various clinicopathological factors was estimated using both the Wilcoxon signed-rank test and logistic regression. The differences in prognosis between patients with high-and low-MYBL2 expression were analyzed via the Kaplan-Meier method and Cox regression analysis. Finally, gene set enrichment analysis (GSEA) was performed to investigate the biofunctions of MYBL2 in ccRCC. It was revealed that MYBL2 was upregulated in ccRCC, and that the MYBL2 high-expression phenotype was significantly associated with sex, a high histological grade, an advanced clinical stage, tumor stage, lymph node metastasis, distant metastasis and poor overall survival (OS). It was also revealed, via the Cox regression analysis, that the upregulation of MYBL2 expression was able to independently predict a poor prognosis in patients with ccRCC. GSEA indicated that the intestinal immune network for IgA production, primary immunodeficiency, the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, the cytosolic DNA-sensing pathway, the p53 signaling pathway and the chemokine signaling pathway were all enriched in the high-MYBL2 expression datasets. In conclusion, the present findings indicate that MYBL2 may be used as an independent prognostic factor in patients with ccRCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Upregulation of MYBL2 independently predicts a poorer prognosis in patients with clear cell renal cell carcinoma

Sun

Lin

2020

Oncol Lett

View full text Add to dashboard Cite

show abstract

“…Beyond "driver" mutations, chronic inflammation is considered to be the MF hallmark. [3][4][5][6][7] More recently, it has been demonstrated that cytokine overproduction in MF myeloid cells is driven by multiple signaling pathways (NF-kB and MAPK) beyond JAK-STAT. 8 Consistently, NF-kB signaling is hyperactivated in MF and contributes to myeloproliferation and inflammation.…”

Section: Introductionmentioning

confidence: 99%

The role of circulating monocytes and JAK inhibition in the infectious-driven inflammatory response of myelofibrosis

et al. 2020

View full text Add to dashboard Cite

Myelofibrosis (MF) is characterized by chronic inflammation and hyper-activation of the JAK-STAT pathway. Infections are one of the main causes of morbidity/mortality. Therapy with Ruxolitinib (RUX), a JAK1/2 inhibitor, may further increase the infectious risk. Monocytes are critical players in inflammation/immunity through cytokine production and release of bioactive extracellular vesicles. However, the functional behavior of MF monocytes, particularly during RUX therapy, is still unclear. In this study, we found that monocytes from JAK2V617F-mutated MF patients show an altered expression of chemokine (CCR2, CXCR3, CCR5) and cytokine (TNF-α-R, IL10-R, IL1β-R, IL6-R) receptors. Furthermore, their ability to produce and secrete free and extracellular vesicles-linked cytokines (IL1β, TNF-α, IL6, IL10) under lipopolysaccharides (LPS) stimulation is severely impaired. Interestingly, monocytes from RUX-treated patients show normal level of chemokine, IL10, IL1β, and IL6 receptors together with a restored ability to produce intracellular and to secrete extracellular vesicles-linked cytokines after LPS stimulation. Conversely, RUX therapy does not normalize TNF-R1/2 receptors expression and the LPS-driven secretion of free pro/antiinflammatory cytokines. Accordingly, upon LPS stimulation, in vitro RUX treatment of monocytes from MF patients increases their secretion of extracellular vesicles-linked cytokines but inhibits the secretion of free pro/anti-inflammatory cytokines. In conclusion, we demonstrated that in MF the infection-driven response of circulating monocytes is defective. Importantly, RUX promotes their infection-driven cytokine production suggesting that infections following RUX therapy may not be due to monocyte failure. These findings contribute to better interpreting the immune vulnerability of MF and to envisaging strategies to improve the infection-driven immune response.

show abstract

“…The resulting activated sets of genes include many inflammatory factors, some of which are secreted into the extracellular space (e.g., CALR [ 16 ]) where they stimulate the local microenvironment. Accordingly, mutation and constitutive activation of JAK2 in MPN is prone to generate an inflammatory milieu inside and outside of the malignant clone [ 17 , 18 , 19 ]. Importantly, chronic inflammation is a risk factor for clonal evolution and may be a trigger of transformation into myelofibrosis (MF) and acute myeloid leukemia (AML) [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms

Chatain

Koschmieder

Jost

2020

Cancers

View full text Add to dashboard Cite

Hematopoiesis is a highly regulated and complex process involving hematopoietic stem cells (HSCs), cell surface adhesion molecules, and cytokines as well as cells of the hematopoietic niche in the bone marrow (BM). Myeloproliferative neoplasms (MPNs) are characterized by clonal expansion of HSCs involving one or more blood cell lineages. Philadelphia-negative MPNs (Ph-neg MPNs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In nearly all patients with Ph-neg MPN, mutations in the genes encoding janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL) can be detected and, together with additional mutations in epigenetic modifier genes, these genetic aberrations contribute to the clonal expansion of the cells. In addition to these intracellular changes in the malignant clone, inflammatory processes involving both the clonal and the non-clonal cells contribute to the signs and symptoms of the patients, as well as to progression of the disease to myelofibrosis (MF) or acute leukemia, and to thrombotic complications. This contribution has been corroborated in preclinical studies including mouse models and patient-derived iPS cells, and in clinical trials, using anti-inflammatory drugs such as JAK inhibitors and steroids, or immunomodulatory drugs such as IMiDs and interferon-alpha (IFNa), all of which change the (im)balance of circulating inflammatory factors (e.g., TNFa, IL-1b, and TGFβ) in MPN. Currently, allogeneic hematopoietic (stem) cell transplantation (allo-HCT) remains the only curative treatment for Ph-neg MPN and is the treatment of choice in intermediate-2 and high-risk MF. HCT can reverse inflammatory changes induced by MPN as well as fibrosis in a large proportion of patients, but it also induces itself profound changes in inflammatory cells and cytokines in the patient, which may help to eradicate the disease but also in part cause significant morbidity (e.g., by graft-versus-host disease). In this review, we focus on the contribution of aberrant inflammation to disease pathogenesis in Ph-neg MPN as well as the current understanding of its alterations after allogeneic HCT.

show abstract

Key Role of Inflammation in Myeloproliferative Neoplasms: Instigator of Disease Initiation, Progression. and Symptoms

Cited by 43 publications

References 76 publications

Upregulation of MYBL2 independently predicts a poorer prognosis in patients with clear cell renal cell carcinoma

Upregulation of MYBL2 independently predicts a poorer prognosis in patients with clear cell renal cell carcinoma

The role of circulating monocytes and JAK inhibition in the infectious-driven inflammatory response of myelofibrosis

Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms

Contact Info

Product

Resources

About