Evolving Therapeutic Strategies for the Classic Philadelphia-Negative Myeloproliferative Neoplasms

Kaplan, Jason; Stein, Brady L.; McMahon, Brandon; Giles, Francis J.; Platanias, Leonidas C.

doi:10.1016/j.ebiom.2016.01.010

Cited by 8 publications

(8 citation statements)

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“…Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) [ 1 , 2 ], with global incidence rates of 0.3–1.5 [ 3 – 5 ], 1.5–2.0 [ 4 – 6 ], and 1.03–2.5 per 100,000/year, respectively [ 3 – 5 ]. These hematopoietic stem cell disorders are characterized by clonal proliferation of ≥ 1 cell type of the myeloid lineages [ 1 , 2 , 7 ] and are associated mostly with mutations in the Janus kinase 2 ( JAK2 ) [ 8 – 10 ], calreticulin ( CALR ) [ 11 , 12 ], or thrombopoietin receptor ( MPL ) genes [ 13 , 14 ]. Clinical manifestations can vary by MPN subtype and can include polycythemia, anemia, leukocytosis, thrombocytosis, fatigue, and hepatosplenomegaly [ 9 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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The impact of myeloproliferative neoplasms (MPNs) on patient quality of life and productivity: results from the international MPN Landmark survey

et al. 2017

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Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) associated with high disease burden, reduced quality of life (QOL), and shortened survival. To assess how MPNs affect patients, we conducted a global MPN Landmark survey. This online survey of patients with MPNs and physicians was conducted in Australia, Canada, Germany, Japan, Italy, and the United Kingdom. The survey measured MPN-related symptoms and the impact of MPNs on QOL and the ability to work as well as disease-management strategies. Overall, 219 physicians and 699 patients (MF, n = 174; PV, n = 223; ET, n = 302) completed the survey; 90% of patients experienced MPN-related symptoms. The most frequent and severe symptom was fatigue. Most patients experienced a reduction in QOL, including those with low symptom burden or low-risk scores. A substantial proportion of patients reported impairment at work and in overall activity. Interestingly, physician feedback and blood counts were the most important indicators of treatment success among patients, with improvements in symptoms and QOL being less important. Regarding disease management, our study revealed a lack of alignment between physician and patient perceptions relating to communication and disease management, with patients often having different treatment goals than physicians. Overall, our study suggested that therapies that reduce symptom burden and improve QOL in patients with MPNs are crucial in minimizing disease impact on patient daily lives. Additionally, our findings showed a need for improved patient-physician communication, standardized monitoring of symptoms, and agreement on treatment goals.

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Section: Introductionmentioning

confidence: 99%

“…In general, patients have an increased risk of thrombotic and thromboembolic events [ 17 ] and have a higher risk of mortality compared with the general population [ 18 – 22 ]. Progression to MF (for those with PV or ET) or acute myeloid leukemia remains a great concern among patients [ 8 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

The impact of myeloproliferative neoplasms (MPNs) on patient quality of life and productivity: results from the international MPN Landmark survey

et al. 2017

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“…Klinik bulgular MPN alt tipine göre değişebilir. Bunlar arasında polisitemi, anemi, lökositoz, trombositoz, yorgunluk ve hepatosplenomegali bulunur (5,12,13). Genel olarak, hastalar trombotik ve tromboembolik olaylarda artmış risk taşırlar ve genel popülasyona göre daha yüksek mortalite riskine sahiptirler (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

Section: Introductionunclassified

“…Genel olarak, hastalar trombotik ve tromboembolik olaylarda artmış risk taşırlar ve genel popülasyona göre daha yüksek mortalite riskine sahiptirler (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). MF'ye (PV veya ET olanlar için) veya akut miyeloid lösemiye ilerlemeler hastalar arasında büyük bir endişe kaynağı olmaya devam etmektedir (5,20). MPN'ler, çoğu hasta için genellikle düşük yaşam kalitesine yol açan hastalıklardır (20)(21)(22)(23)(24).…”

Section: Introductionunclassified

Effect of CXCR9-CXCR3 Cytokine Signaling Pathway in Polycytemia Vera

Altunay¹,

Yavuz²,

Tokdemir³

2019

Experimed

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Amaç: Miyeloproliferatif Neoplaziler (MPN), miyeloproliferatif bozukluklar arasında en sık görülen hastalıklardandır. Tamamen işlevsel olan ve son aşamaya kadar farklılaşmış kan hücrelerinin aşırı üretimi ile karakterize edilirler. Önceki çalışmalarda Granülosit-Makrofaj Koloni Uyarıcı Faktörün (GM-CSF) sağlıklı hematopoietik kök hücreler (HKH)'de proliferasyon kontrolünden sorumlu CXCR3 ekspresyonunu arttırdığı gösterilmiştir. Bu çalışmanın amacı, CXCL9-CXCR3 sinyal yolağının MPN progresyonunda etkisinin araştırılmasıdır. Gereç ve Yöntem: Çalışmada, MPN ve sağlıklı insan perifer kan mononükleer hücrelerinde (MNH) ve kanser HKH de CXCL9 kemokini ve bunun reseptörü olan CXCR3'ün iki izoformunun (CXCR3A ve CXCR3B) gen ifade seviyeleri, MNH yüzeyinde ise CXCR3 reseptör varlığı incelenmiştir. Ekspresyon seviyelerini araştırmak amacıyla kantitatif gerçek zamanlı polimeraz zincir reaksiyonu (PZR), hücre yüzey reseptör durumunun incelenmesi içinse akım ölçer metotları kullanılmıştır. GM-CSF'in MNH ve CD34+ hücrelerinde uygulamasının ardından CXCR3 ekspresyonu değerlendirilmiştir. Bulgular: MNH'de CXCR3A ifadesinin hastalarda sağlıklılara göre istatistiksel olarak anlamlı arttığı bulunmuşur. Hasta ve sağlıklı kontrol grupları arasında CXCR3B ve CXCL9 ifade seviyeleri kıyaslandığında istatistiksel olarak anlamlı bir fark olmadığı tespit edilmiştir. CXCR3 Hücre yüzey reseptör durumuna bakıldığında ise hastalardan elde edilen MNH'deki anlatımda sağlıklı gruptan elde edilenlere göre anlamlı bir azalma olduğu görülmüştür. Sonuç: Bu sonuçlar MPN'de CXCR3A/CXCR3B dengesi ile bu reseptörlere özgün olarak bağlanan kemokinler CXCL9, CXCL10 ve CXCL11'in inflamasyon ve kanser progresyonu ile ilişkili olabileceğini düşündürmektedir.

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“…JAK inhibitors ameliorate symptoms and reduce splenomegaly, but cannot control the disease burden. Given the limitation of JAK inhibition as monotherapy (Kaplan, et al 2016), novel treatment strategies are needed.…”

Section: Hdac8: a New Therapeutic Target?mentioning

confidence: 99%

Role of Mesenchymal Stromal Cells and their Extracellular Vesicles microRNAs in JAK2 Myeloproliferative Neoplasms

Ramos¹,

Conceiçao²

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Compared to HD, BM-MSC from MPN patients showed similar morphology and differentiation capacity, with an increased proliferation rate with less apoptotic cells. BM-MSC from MPN expressed comparable levels of CD73, CD44, CD90 and CD166, whereas they were negative for haematopoietic markers. The median expression of CD105 was lower in BM-MSC from MPN patients (p <0.05) when compared to controls. Gene expression profile of BM-MSC showed a total of 169 genes that were differentially expressed in BM-MSC from MPN patients compared to HD. RT-PCR was performed in two genes to confirm these results, demonstrating that HDAC8 and MYADM genes were upregulated. Next, we observed a significant increase in the number of CFU-GM when MPN-HPC were co-cultured with MPN-MSC compared to HD-MSC. MPN-MSC also showed the ability to support healthy HPC in LTBMC. However, MPN-MSC showed alterations in the expression of genes associated to the maintenance of haematopoiesis. The inhibition of HDAC8 in BM-MSC from MPN was confirmed by RT-PCR and WB assays, when the cells were treated with PCI34051. HDAC8-selective inhibition also induced a cell cycle arrest in the MPN BM-MSC, with an increase of the percentage of apoptotic cells. Co-cultures of BM-MNC from MPN patients with neoplastic stroma previously treated with HDAC8 inhibitor induced a decrease in MNC cell viability (p=0.028), CFU-GM (p=0.018) and an increase of TP53 expression. Regarding the EV studies, we showed that the characterisation by TEM and NanoSight revealed that EV-MSC from both groups exhibited a size and morphology characteristic of EV, and were positive for CD63 (WB), the characteristic marker of EV. By MFC, EV released from BM-MSC of both groups (HD and JAK2) were defined as particles less than 1µM of diameter, positive for CD90, CD44 and CD73 and for EV markers. At the same time they were negative for CD34 and CD45, demonstrating the specificity of monoclonal labelling. When the content of microRNA was analysed (8 HD-MSC and 11 MPN-MSC), we observed an overall increase in the microRNA expression in the EV from patients, yet without reaching statistical significance. Using RT-PCR, we observed a significant overexpression (p=0.032) of miR-155 in the EV derived from MPN-MSC. We also observed an increase of CD34+ cell viability, after the incorporation of EV from both groups (HD and JAK2). A significant increase (p=0.04) of miR-155 expression was observed in the HD CD34+ cells, after incorporating MPN-MSC-derived EV. In addition, an increase of CFU-GM was observed when neoplastic CD34+ cells incorporated the EV derived from MSC from MPN patients (p=0.056). Conclusions These results suggest that MPN-MSC display different proliferative rate, immunophenotypic markers, gene expression profile and HDAC8 overexpression compared to HD-MSC. The inhibition of HDAC8 expression by its specific inhibitor decreases the capacity of the stroma to support haematopoietic cells from MPN patients, suggesting that HDAC8 may be a potential therapeutic target. Furthermore, we suggest that EV rel...

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Evolving Therapeutic Strategies for the Classic Philadelphia-Negative Myeloproliferative Neoplasms

Cited by 8 publications

References 106 publications

The impact of myeloproliferative neoplasms (MPNs) on patient quality of life and productivity: results from the international MPN Landmark survey

The impact of myeloproliferative neoplasms (MPNs) on patient quality of life and productivity: results from the international MPN Landmark survey

Effect of CXCR9-CXCR3 Cytokine Signaling Pathway in Polycytemia Vera

Role of Mesenchymal Stromal Cells and their Extracellular Vesicles microRNAs in JAK2 Myeloproliferative Neoplasms

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