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Myeloproliferation

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https://www.readbyqxmd.com/read/28637883/niche-mediated-depletion-of-the-normal-hematopoietic-stem-cell-reservoir-by-flt3-itd-induced-myeloproliferation
#1
Adam J Mead, Wen Hao Neo, Nikolaos Barkas, Sahoko Matsuoka, Alice Giustacchini, Raffaella Facchini, Supat Thongjuea, Lauren Jamieson, Christopher A G Booth, Nicholas Fordham, Cristina Di Genua, Deborah Atkinson, Onima Chowdhury, Emmanouela Repapi, Nicki Gray, Shabnam Kharazi, Sally-Ann Clark, Tiphaine Bouriez, Petter Woll, Toshio Suda, Claus Nerlov, Sten Eirik W Jacobsen
Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment...
July 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28536276/persistent-immune-stimulation-exacerbates-genetically-driven-myeloproliferative-disorders-via-stromal-remodeling
#2
Claudio Tripodo, Alessia Burocchi, Pier Paolo Piccaluga, Claudia Chiodoni, Paola Portararo, Barbara Cappetti, Laura Botti, Alessandro Gulino, Alessandro Isidori, Arcangelo Liso, Giuseppe Visani, Maria Paola Martelli, Brunangelo Falini, Pier Paolo Pandolfi, Mario P Colombo, Sabina Sangaletti
Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with downregulation of secreted protein acidic and rich in cysteine (SPARC) and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells...
May 23, 2017: Cancer Research
https://www.readbyqxmd.com/read/28499938/allogeneic-stem-cell-transplantation-in-myelofibrosis
#3
REVIEW
Tania Jain, Ruben A Mesa, Jeanne M Palmer
Myeloproliferative neoplasm (MPN) is a category in the World Health Organization classification of myeloid tumors. BCR-ABL1-negative MPN is a subcategory that includes primary myelofibrosis (MF), post-essential thrombocythemia MF, and post-polycythemia vera MF. These disorders are characterized by stem cell-derived clonal myeloproliferation. Clinically, these diseases present with anemia and splenomegaly and significant constitutional symptoms such as severe fatigue, symptoms associated with an enlarged spleen and liver, pruritus, fevers, night sweats, and bone pain...
May 10, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28423484/mir-494-3p-overexpression-promotes-megakaryocytopoiesis-in-primary-myelofibrosis-hematopoietic-stem-progenitor-cells-by-targeting-socs6
#4
Sebastiano Rontauroli, Ruggiero Norfo, Valentina Pennucci, Roberta Zini, Samantha Ruberti, Elisa Bianchi, Simona Salati, Zelia Prudente, Chiara Rossi, Vittorio Rosti, Paola Guglielmelli, Giovanni Barosi, Alessandro Vannucchi, Enrico Tagliafico, Rossella Manfredini
Primary myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by hematopoietic stem cell-derived clonal myeloproliferation, involving especially the megakaryocyte lineage. To better characterize how the altered expression of microRNAs might contribute to PMF pathogenesis, we have previously performed the integrative analysis of gene and microRNA expression profiles of PMF hematopoietic stem/progenitor cells (HSPCs), which allowed us to identify miR-494-3p as the upregulated microRNA predicted to target the highest number of downregulated mRNAs...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28405618/efficacy-of-alk5-inhibition-in-myelofibrosis
#5
Lanzhu Yue, Matthias Bartenstein, Wanke Zhao, Wanting Tina Ho, Ying Han, Cem Murdun, Adam W Mailloux, Ling Zhang, Xuefeng Wang, Anjali Budhathoki, Kith Pradhan, Franck Rapaport, Huaquan Wang, Zonghong Shao, Xiubao Ren, Ulrich Steidl, Ross L Levine, Zhizhuang Joe Zhao, Amit Verma, Pearlie K Epling-Burnette
Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28401746/resolution-of-liver-disease-in-transient-abnormal-myelopoiesis-with-fish-oil-emulsion
#6
Toshihiko Watanabe, Shoichiro Amari, Keiko Tsukamoto, Yushi Ito, Daisuke Tomizawa, Takako Yoshioka, Yutaka Kanamori
Neonates with Down syndrome are at risk of developing transient abnormal myelopoiesis (TAM), which is characterized by transient clonal myeloproliferation of the blast cells. TAM can resolve spontaneously, but some patients die at an early age due to organ failure. Liver fibrosis in TAM is a life-threatening condition, but treatment options have not yet been established. Here, we report on the case of an infant with TAM complicated by liver disease, whose hyperbilirubinemia was successfully ameliorated with omega-3 fatty acid (ω3FA) lipid emulsion...
April 2017: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/28360416/heterodimerization-of-aml1-eto-with-cbf%C3%AE-is-required-for-leukemogenesis-but-not-for-myeloproliferation
#7
V Thiel, B D Giaimo, P Schwarz, K Soller, V Vas, M Bartkuhn, T J Blätte, K Döhner, L Bullinger, T Borggrefe, H Geiger, F Oswald
The AML1/Runx1 transcription factor and its heterodimerization partner CBFβ are essential regulators of myeloid differentiation. The chromosomal translocation t(8;21), fusing the DNA binding domain of AML1 to the corepressor eight-twenty-one (ETO), is frequently associated with acute myeloid leukemia (AML) and generates the AML1/ETO (AE) fusion protein. AE represses target genes usually activated by AML1 and also affects the endogenous repressive function of ETO at Notch target genes. In order to analyze the contribution of CBFβ in AE-mediated leukemogenesis and deregulation of Notch target genes, we introduced two point mutations in a leukemia initiating version of AE in mice, called AE9a, that disrupt the AML1/CBFβ interaction (AE9aNT)...
March 31, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28259826/medical-management-of-extensive-arterial-thromboembolism-in-a-patient-with-essential-thrombocythemia-and-warfarin-failure
#8
Aisha K Ahmed, Alicia Youssef, Nedaa Skeik
Chronic myeloproliferative disorders share a stem cell-derived clonal myeloproliferation. This group of disorders include essential thrombocythemia (ET), polycythemia vera (PV), chronic myeloid leukemia, and primary myelofibrosis (PMF), with the respective features of thrombocytosis, erythrocytosis, and bone marrow fibrosis. These disorders can be associated with genetic mutations affecting protein tyrosine kinases, resulting in different configurations of abnormal signal transduction. The Janus tyrosine kinase 2 mutation can be used as a key diagnostic tool for diagnosing MPDs, specifically, ET, PV, and PMF...
March 1, 2017: Annals of Vascular Surgery
https://www.readbyqxmd.com/read/28213513/runx1-cooperates-with-flt3-itd-to-induce-leukemia
#9
Kira Behrens, Katrin Maul, Nilgün Tekin, Neele Kriebitzsch, Daniela Indenbirken, Vladimir Prassolov, Ursula Müller, Hubert Serve, Jörg Cammenga, Carol Stocking
Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27966016/austrian-recommendations-for-the-management-of-primary-myelofibrosis-post-polycythemia-vera-myelofibrosis-and-post-essential-thrombocythemia-myelofibrosis-an-expert-statement
#10
Thamer Sliwa, Christine Beham-Schmid, Sonja Burgstaller, Veronika Buxhofer-Ausch, Günther Gastl, Klaus Geissler, Maria Krauth, Peter Krippl, Alois Lang, Andreas Petzer, Stefan Wöhrer, Albert Wölfler, Heinz Gisslinger
The entity "myelofibrosis" represents a subgroup of the Philadelphia chromosome-negative myeloproliferative neoplasms. It comprises primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. This heterogeneous disease is characterized by clonal myeloproliferation, dysregulated kinase signalling and the abnormal expression of several proinflammatory cytokines. Clinically, patients present with symptoms related to thrombocytosis/leukocytosis, anemia and/or progressive splenomegaly...
May 2017: Wiener Klinische Wochenschrift
https://www.readbyqxmd.com/read/27884555/after-10years-of-jak2v617f-disease-biology-and-current-management-strategies-in-polycythaemia-vera
#11
REVIEW
Jacob Grinfeld, Anna L Godfrey
The JAK2V617F mutation accounts for the vast majority of patients with polycythaemia vera (PV) and around half of those with other Philadelphia-negative myeloproliferative neoplasms. Since its discovery in 2005, numerous insights have been gained into the pathways by which JAK2V617F causes myeloproliferation, including activation of JAK-STAT signalling but also through other canonical and non-canonical pathways. A variety of mechanisms explain how this one mutation can be associated with distinct clinical disorders, demonstrating how constitutional and acquired factors may interact in the presence of a single mutation to determine disease phenotype...
May 2017: Blood Reviews
https://www.readbyqxmd.com/read/27870387/primary-myelofibrosis-2017-update-on-diagnosis-risk-stratification-and-management
#12
REVIEW
Ayalew Tefferi
Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR or MPL mutation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression and shortened survival. DIAGNOSIS: Diagnosis is based on bone marrow morphology. The presence of JAK2, CALR or MPL mutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are "triple-negative...
December 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27546516/plasma-tgf-%C3%AE-1-levels-are-elevated-in-down-syndrome-infants-with-transient-abnormal-myelopoiesis
#13
Hajime Maeda, Hayato Go, Takashi Imamura, Maki Sato, Nobuo Momoi, Mitsuaki Hosoya
Infants with Down syndrome (DS) are at risk of developing a transient myeloproliferative disorder during the neonatal period, known as transient abnormal myelopoiesis (TAM). It is characterized by clonal myeloproliferation and is typically self-limiting. However, TAM can be a life-threatening disorder, when complicated by liver fibrosis. Here, we evaluated cytokine profiles in two male DS infants having TAM with or without liver dysfunction. The first patient, Patient 1, had hyperleukocytosis with cholestatic liver dysfunction, coagulopathy, and increased counts of blasts and was treated with exchange transfusion (ExT) due to the serious general condition...
2016: Tohoku Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27486814/nucleophosmin-leukemogenic-mutant-activates-wnt-signaling-during-zebrafish-development
#14
Elisa Barbieri, Gianluca Deflorian, Federica Pezzimenti, Debora Valli, Marco Saia, Natalia Meani, Alicja M Gruszka, Myriam Alcalay
Nucleophosmin (NPM1) is a ubiquitous multifunctional phosphoprotein with both oncogenic and tumor suppressor functions. Mutations of the NPM1 gene are the most frequent genetic alterations in acute myeloid leukemia (AML) and result in the expression of a mutant protein with aberrant cytoplasmic localization, NPMc+. Although NPMc+ causes myeloproliferation and AML in animal models, its mechanism of action remains largely unknown. Here we report that NPMc+ activates canonical Wnt signaling during the early phases of zebrafish development and determines a Wnt-dependent increase in the number of progenitor cells during primitive hematopoiesis...
August 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27427906/context-matters-distinct-disease-outcomes-as-a-result-of-crebbp-hemizygosity-in-different-mouse-bone-marrow-compartments
#15
Ting Zhou, Stephanie N Perez, Ziming Cheng, Marsha C Kinney, Madeleine E Lemieux, Linda M Scott, Vivienne I Rebel
Perturbations in CREB binding protein (CREBBP) are associated with hematopoietic malignancies, including myelodysplastic syndrome (MDS). Mice hemizygous for Crebbp develop myelodysplasia with proliferative features, reminiscent of human MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U), and a proportion goes on to develop acute myeloid leukemia (AML). We have also shown that the Crebbp+/- non-hematopoietic bone marrow microenvironment induces excessive myeloproliferation of wild-type cells. We now report that transplantation of unfractionated Crebbp+/- bone marrow into wild-type recipients resulted in either early-onset AML or late-onset MDS and MDS/MPN-U...
2016: PloS One
https://www.readbyqxmd.com/read/27411587/ripk3-restricts-myeloid-leukemogenesis-by-promoting-cell-death-and-differentiation-of-leukemia-initiating-cells
#16
Ulrike Höckendorf, Monica Yabal, Tobias Herold, Enkhtsetseg Munkhbaatar, Stephanie Rott, Stefanie Jilg, Johanna Kauschinger, Giovanni Magnani, Florian Reisinger, Michael Heuser, Hans Kreipe, Karl Sotlar, Thomas Engleitner, Roland Rad, Wilko Weichert, Christian Peschel, Jürgen Ruland, Mathias Heikenwalder, Karsten Spiekermann, Julia Slotta-Huspenina, Olaf Groß, Philipp J Jost
Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1(-/-), Pycard(-/-), and Tnfr1/2(-/-) mice...
July 11, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27282563/the-expression-of-death-inducer-obliterator-dido-variants-in-myeloproliferative-neoplasms
#17
Maria Gabriela Berzoti-Coelho, Aline Fernanda Ferreira, Natalia de Souza Nunes, Mariana Tomazini Pinto, Maurício Cristiano Rocha Júnior, Belinda Pinto Simões, Carlos Martínez-A, Elizabeth Xisto Souto, Rodrigo Alexandre Panepucci, Dimas Tadeu Covas, Simone Kashima, Fabíola Attié Castro
Chronic Myeloid Leukemia (CML), Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are Myeloproliferative Neoplasms (MPN) characterized by clonal myeloproliferation without cell maturation impairment. CML pathogenesis is associated with the Ph chromosome leading to BCR-ABL tyrosine-kinase constitutive expression. The Ph negative MPN (PV, ET and PMF) are characterized by the mutation JAK2(V617F) of the JAK2 protein in the auto-inhibitory JH2 domain, which is found in most PV patients and in approximately half of ET and PMF patients...
July 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/27229714/characterization-of-leukemias-with-etv6-abl1-fusion
#18
Marketa Zaliova, Anthony V Moorman, Giovanni Cazzaniga, Martin Stanulla, Richard C Harvey, Kathryn G Roberts, Sue L Heatley, Mignon L Loh, Marina Konopleva, I-Ming Chen, Olga Zimmermannova, Claire Schwab, Owen Smith, Marie-Joelle Mozziconacci, Christian Chabannon, Myungshin Kim, J H Frederik Falkenburg, Alice Norton, Karen Marshall, Oskar A Haas, Julia Starkova, Jan Stuchly, Stephen P Hunger, Deborah White, Charles G Mullighan, Cheryl L Willman, Jan Stary, Jan Trka, Jan Zuna
To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing...
September 2016: Haematologica
https://www.readbyqxmd.com/read/27183638/dok1-and-dok2-proteins-regulate-cell-cycle-in-hematopoietic-stem-and-progenitor-cells
#19
Emilie Coppin, Maria De Grandis, Pier Paolo Pandolfi, Marie-Laure Arcangeli, Michel Aurrand-Lions, Jacques A Nunès
Dok1 and Dok2 proteins play a crucial role in myeloid cell proliferation as demonstrated by Dok1 and Dok2 gene inactivation, which induces a myeloproliferative disease in aging mice. In this study, we show that Dok1/Dok2 deficiency affects myeloproliferation even at a young age. An increase in the cellularity of multipotent progenitors is observed in young Dok1/Dok2-deficient mice. This is associated with an increase in the cells undergoing cell cycle, which is restricted to myeloid committed progenitors. Furthermore, cellular stress triggered by 5-fluorouracil (5-FU) treatment potentiates the effects of the loss of Dok proteins on multipotent progenitor cell cycle...
May 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27134742/recent-advances-in-understanding-myelofibrosis-and-essential-thrombocythemia
#20
REVIEW
William Vainchenker, Stefan N Constantinescu, Isabelle Plo
The classic BCR-ABL-negative myeloproliferative neoplasms (MPNs), a form of chronic malignant hemopathies, have been classified into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). ET and PMF are two similar disorders in their pathogenesis, which is marked by a key role of the megakaryocyte (MK) lineage. Whereas ET is characterized by MK proliferation, PMF is also associated with aberrant MK differentiation (myelodysplasia), leading to the release of cytokines in the marrow environment, which causes the development of myelofibrosis...
2016: F1000Research
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