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| Open AccessTamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis
Preclinical studies indicate that myeloproliferative neoplasms (MPN) may be sensitive to the estrogen receptor modulator, tamoxifen. Here, the authors present a phase II clinical trial reporting the efficacy of tamoxifen in MPN and analysis of peripheral haematopoietic stem cells to identify potential predictive signatures of responders.
- Zijian Fang
- , Giuditta Corbizi Fattori
- & Simón Méndez-Ferrer
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Article
| Open AccessProteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis
Myelofibrosis is a form of myeloproliferative neoplasm with few treatment options available. Here, the authors profiled drug responses and proteomics ex vivo and identify molecularly-guided treatment strategies, including HDAC and BET inhibitors for CALR mutant myelofibrosis patients.
- Mattheus H. E. Wildschut
- , Julien Mena
- & Berend Snijder
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Article
| Open AccessOncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation
In myeloproliferative neoplasms, frameshift mutants of calreticulin turn into rogue cytokines by inducing constitutive activation of the Thrombopoietin Receptor (TpoR). Here, the authors define how mutant calreticulin acquires specificity for TpoR binding and triggers its constitutive activation.
- Nicolas Papadopoulos
- , Audrey Nédélec
- & Stefan N. Constantinescu
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Article
| Open AccessInhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies
Hypomethylating agents, such as 5-Azacytidine (5-AZA), are standard of care for patients with myelodysplastic and myeloid malignancies, however response rates are limited and risk of relapses high. Here the authors show that inhibition of lysyl oxidases synergizes with 5-AZA to improve erythropoiesis and reduce disease burden in myelodysplastic neoplasms models.
- Qingyu Xu
- , Alexander Streuer
- & Daniel Nowak
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Article
| Open AccessHOXA9 has the hallmarks of a biological switch with implications in blood cancers
HOXA9 plays an important role in acute myeloid leukaemia (AML), but its relevance for other blood malignancies is unclear. Here, the authors show that HOXA9 has a binary switch function that can clinically stratify AML patients, and model how the interactions with JAK2, TET2 and NOTCH impact myeloproliferative neoplasms.
- Laure Talarmain
- , Matthew A. Clarke
- & Benjamin A. Hall
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Article
| Open AccessInterleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm
Chronic inflammation is frequently observed in patients with myeloproliferative neoplasms (MPN). Here the authors observe elevated levels of IL-1α and IL-1β in MPN patients and show that IL-1 contributes to clonal expansion and bone marrow fibrosis in a mouse model of MPN, proposing targeting of IL1R1 as therapeutic intervention.
- Mohammed Ferdous-Ur Rahman
- , Yue Yang
- & Golam Mohi
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| Open AccessInhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm
Inflammatory cytokines are elevated in patients with myeloproliferative neoplasms (MPN). Here the authors show that the JAK2-V617F mutation is associated with increased expression of IL-1 in MPN patients and that loss of IL-1β in JAK2-V617F mutant hematopoietic cells reduces MPN symptoms and myelofibrosis in a mouse model.
- Shivam Rai
- , Elodie Grockowiak
- & Radek C. Skoda
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Article
| Open AccessGermline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis
Myelofibrosis is a risk factor for the development of Acute Myeloid Leukaemia. Here, the authors carry out an integrated genomic investigation of 933 myelofibrosis patients, and identified interactions between germline and somatic variation in patients who required haematopoietic cell transplantation.
- Derek W. Brown
- , Weiyin Zhou
- & Mitchell J. Machiela
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| Open AccessA lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy
Combination therapies simultaneously inhibiting different therapeutic targets in cancer is challenged by individual pharmacokinetic profiles. Here, the authors generate an orally provided multi-targeted kinase inhibitor that is lymphatic absorbed and increases survival in a murine model of myelofibrosis.
- Brian D. Ross
- , Youngsoon Jang
- & Marcian E. Van Dort
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| Open AccessDiscovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Interferon alpha (IFNalpha) therapy is showing promising results to treat myeloproliferative neoplasms (MPNs). Here, the authors show that IFNalpha response requires ULK1 phosphorylation to induce p38-MAPK signalling but it is counteracted by ROCK1-2 activation suggesting combination therapy of IFNalpha-ROCK1-2 inhibition may improve MPNs treatment.
- Diana Saleiro
- , Jeremy Q. Wen
- & Leonidas C. Platanias
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| Open AccessMastocytosis-derived extracellular vesicles deliver miR-23a and miR-30a into pre-osteoblasts and prevent osteoblastogenesis and bone formation
Osteoporosis and bone disease are common in patients with systemic mastocytosis. Here, the authors show that extracellular vesicles released by neoplastic mast cells of the patients block osteoblast differentiation and bone mineralization when injected into mice, via a mechanism involving suppression of osteogenic factors via miRNA-30a and miRNA-23a.
- Do-Kyun Kim
- , Geethani Bandara
- & Ana Olivera
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Article
| Open AccessCalreticulin del52 and ins5 knock-in mice recapitulate different myeloproliferative phenotypes observed in patients with MPN
Calreticulin del52 and ins5 mutations induce two phenotypically distinct myeloproliferative neoplasms in patients. Here the authors show that modeling these mutations in knock-in mice recapitulate the two diseases and highlight how they impact the different hematopoietic compartments.
- Camélia Benlabiod
- , Maira da Costa Cacemiro
- & Caroline Marty
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| Open AccessOncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation
Oncogenic Ras mutations are common drivers in myeloid leukemia. Here, the authors show in patient cells and in mice that oncogenic K-Ras activates NLRP3 inflammasome to drive myeloproliferation, which can be reversed by genetic or pharmacologic NLRP3 blockade.
- Shaima’a Hamarsheh
- , Lena Osswald
- & Robert Zeiser
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Article
| Open AccessHSP27 is a partner of JAK2-STAT5 and a potential therapeutic target in myelofibrosis
Myelofibrosis is a chronic degenerative disorder characterized by progressive bone marrow fibrosis. Here, the authors show that the chaperone HSP27 contributes to myelofibrosis via regulation of the JAK2/STAT5 pathway, and that antisense oligonucleotides targeting HSP27 are effective in two mouse models of the disease
- Margaux Sevin
- , Lucia Kubovcakova
- & Aurélie de Thonel
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| Open AccessRAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia (JMML) is an aggressive disease with limited options for treatment. Here, the authors analyse the DNA methylome and mutational profile of JMML to define three subgroups with unique molecular and clinical characteristics.
- Daniel B. Lipka
- , Tania Witte
- & Christoph Plass
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| Open AccessGenome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia (JMML) is an aggressive disease with limited options for treatment. Here, the authors utilize DNA methylation based subgroups in JMML to predict clinical outcome.
- Elliot Stieglitz
- , Tali Mazor
- & Mignon L. Loh
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| Open AccessTet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells
TET2 catalyses DNA demethylation and is mutated in various blood cancers; in particularTet2null mice develop haematological neoplasms. Here the authors show that this effect could be due to the increased frequency of mutation associated with TET2 loss in haematopoietic stem/progenitor cells.
- Feng Pan
- , Thomas S. Wingo
- & Mingjiang Xu
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| Open AccessGenetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms
Somatic mutations drive the clonal proliferation of myeloproliferative neoplasms. Here the authors conduct a genome-wide association study and identify germline variation at multiple loci associated with the development and disease phenotype of these cancers.
- William Tapper
- , Amy V. Jones
- & Nicholas C.P. Cross
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Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease
The histone methyltransferase Ezh2 is thought to have a dual function both as a tumour suppressor and an oncogene. Using mouse models with Ezh2 gain-of-function, Herrera-Merchanet al. show that Ezh2 expression in HSCs severely compromises hematopoietic function, leading to myeloproliferative disease.
- A. Herrera-Merchan
- , L. Arranz
- & S. Gonzalez