Myeloproliferative Neoplasms

Reuther, Gary W.

doi:10.1016/bs.pmbts.2016.09.004

Cited by 5 publications

(2 citation statements)

References 195 publications

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“…In recent years, investigation on MPNs revealed that there are three driver mutations (JAK2, MPL and CALR) essential as clonal markers, activating the cytokine receptor JAK2 signaling pathway and the downstream effectors (30,57).…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

et al. 2017

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Abstract. Myeloproliferative neoplasms (MPNs) result from the malignant transformation of a hematopoietic stem-cell (HSC), leading to abnormal amplification and proliferation of myeloid lineages. Identification of the Janus kinase 2 (JAK2) V617F mutation developed the knowledge of Philadelphia-negative (PN)-MPNs, contributing to and influencing the definition of the phenotype and prognostic impact. Considering the lack of Portuguese epidemiological data, the present study intends to characterize the prevalence of the JAK2 mutation in a PN-MPN versus a control Portuguese population. Caucasian Portuguese PN-MPN patients (n=133) and 281 matched control subjects were investigated. No significant differences were identified between the case and control groups concerning age distribution or smoking habits. Pathology distribution was as follows: 60.2% with essential thrombocythemia (ET), 29.3% with polycythemia vera (PV) and 10.5% with primary myelofibrosis (PMF). A total of 75.0% of patients were positive for the presence of the JAK2 V617F mutation. In addition, the prevalence of PV was 87.2%, ET was 73.4% and PMF was 50.0%. The JAK2 V617F mutation is observed in various MPN phenotypes, and has an increased incidence in ET patients and a decreased incidence in PV patients. These data may contribute to improving the knowledge of the pathophysiology of these disorders, and to a more rational and efficient selection of therapeutic strategies to be adopted, notably because most of the patients are JAK2 V617F negative.

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Section: Discussionmentioning

confidence: 99%

“…In MPN patients, even in the absence of the JAK2 mutation, the other genetic changes result in activation of the JAK2 signaling pathway (30).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

et al. 2017

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Myeloproliferative Neoplasms

Méndez‐Ferrer¹,

Fang²

2023

Encyclopedia of Cell Biology

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Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies

Liang

Zang

et al. 2019

J. Med. Chem.

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Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Here, a novel series of pyrimidin-2-aminopyrazol hydroxamate derivatives as JAK and HDAC dual inhibitors was designed, synthesized, and evaluated, among which 8m possessed potent and balanced activities against both JAK2 and HDAC6 with half-maximal inhibitory concentration at the nanomolar level. 8m exhibited improved antiproliferative and proapoptotic activities over SAHA and ruxolitinib in several hematological cell lines. Remarkably, 8m exhibited more potent antiproliferation effect than the combination of SAHA and ruxolitinib in HEL cells bearing JAK2 V617F mutation. Pharmacokinetic studies in mice showed that 8m possessed good bioavailability after intraperitoneal administration. Finally, 8m showed antitumor efficacy with no significant toxicity in a HEL xenograft model. Collectively, the results confirm the therapeutic potential of JAK and HDAC dual inhibitors in hematological malignancies and provide valuable leads for further structural optimization and antitumor mechanism study.

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Myeloproliferative Neoplasms

Cited by 5 publications

References 195 publications

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

Myeloproliferative Neoplasms

Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies

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