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https://www.readbyqxmd.com/read/26547506/integrative-analysis-of-copy-number-and-gene-expression-data-suggests-novel-pathogenetic-mechanisms-in-primary-myelofibrosis
#1
Simona Salati, Roberta Zini, Simona Nuzzo, Paola Guglielmelli, Valentina Pennucci, Zelia Prudente, Samantha Ruberti, Sebastiano Rontauroli, Ruggiero Norfo, Elisa Bianchi, Costanza Bogani, Giada Rotunno, Tiziana Fanelli, Carmela Mannarelli, Vittorio Rosti, Silvia Salmoiraghi, Daniela Pietra, Sergio Ferrari, Giovanni Barosi, Alessandro Rambaldi, Mario Cazzola, Silvio Bicciato, Enrico Tagliafico, Alessandro M Vannucchi, Rossella Manfredini
Primary myelofibrosis (PMF) is a Myeloproliferative Neoplasm (MPN) characterized by megakaryocyte hyperplasia, progressive bone marrow fibrosis, extramedullary hematopoiesis and transformation to Acute Myeloid Leukemia (AML). A number of phenotypic driver (JAK2, CALR, MPL) and additional subclonal mutations have been described in PMF, pointing to a complex genomic landscape. To discover novel genomic lesions that can contribute to disease phenotype and/or development, gene expression and copy number signals were integrated and several genomic abnormalities leading to a concordant alteration in gene expression levels were identified...
April 1, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/25097177/mirna-mrna-integrative-analysis-in-primary-myelofibrosis-cd34-cells-role-of-mir-155-jarid2-axis-in-abnormal-megakaryopoiesis
#2
Ruggiero Norfo, Roberta Zini, Valentina Pennucci, Elisa Bianchi, Simona Salati, Paola Guglielmelli, Costanza Bogani, Tiziana Fanelli, Carmela Mannarelli, Vittorio Rosti, Daniela Pietra, Silvia Salmoiraghi, Andrea Bisognin, Samantha Ruberti, Sebastiano Rontauroli, Giorgia Sacchi, Zelia Prudente, Giovanni Barosi, Mario Cazzola, Alessandro Rambaldi, Stefania Bortoluzzi, Sergio Ferrari, Enrico Tagliafico, Alessandro M Vannucchi, Rossella Manfredini
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by megakaryocyte (MK) hyperplasia, bone marrow fibrosis, and abnormal stem cell trafficking. PMF may be associated with somatic mutations in JAK2, MPL, or CALR. Previous studies have shown that abnormal MKs play a central role in the pathophysiology of PMF. In this work, we studied both gene and microRNA (miRNA) expression profiles in CD34(+) cells from PMF patients. We identified several biomarkers and putative molecular targets such as FGR, LCN2, and OLFM4...
September 25, 2014: Blood
https://www.readbyqxmd.com/read/24986690/clinical-effect-of-driver-mutations-of-jak2-calr-or-mpl-in-primary-myelofibrosis
#3
Elisa Rumi, Daniela Pietra, Cristiana Pascutto, Paola Guglielmelli, Alejandra Martínez-Trillos, Ilaria Casetti, Dolors Colomer, Lisa Pieri, Marta Pratcorona, Giada Rotunno, Emanuela Sant'Antonio, Marta Bellini, Chiara Cavalloni, Carmela Mannarelli, Chiara Milanesi, Emanuela Boveri, Virginia Ferretti, Cesare Astori, Vittorio Rosti, Francisco Cervantes, Giovanni Barosi, Alessandro M Vannucchi, Mario Cazzola
We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes...
August 14, 2014: Blood
https://www.readbyqxmd.com/read/24553179/calr-exon-9-mutations-are-somatically-acquired-events-in-familial-cases-of-essential-thrombocythemia-or-primary-myelofibrosis
#4
Elisa Rumi, Ashot S Harutyunyan, Daniela Pietra, Jelena D Milosevic, Ilaria C Casetti, Marta Bellini, Nicole C C Them, Chiara Cavalloni, Virginia V Ferretti, Chiara Milanesi, Tiina Berg, Emanuela Sant'Antonio, Emanuela Boveri, Cristiana Pascutto, Cesare Astori, Robert Kralovics, Mario Cazzola
Somatic mutations in the calreticulin (CALR) gene were recently discovered in patients with sporadic essential thrombocythemia (ET) and primary myelofibrosis (PMF) lacking JAK2 and MPL mutations. We studied CALR mutation status in familial cases of myeloproliferative neoplasm. In a cohort of 127 patients, CALR indels were identified in 6 of 55 (11%) subjects with ET and in 6 of 20 (30%) with PMF, whereas 52 cases of polycythemia vera had nonmutated CALR. All CALR mutations were somatic, found in granulocytes but not in T lymphocytes...
April 10, 2014: Blood
https://www.readbyqxmd.com/read/24458439/impact-of-mutational-status-on-outcomes-in-myelofibrosis-patients-treated-with-ruxolitinib-in-the-comfort-ii-study
#5
RANDOMIZED CONTROLLED TRIAL
Paola Guglielmelli, Flavia Biamonte, Giada Rotunno, Valentina Artusi, Lucia Artuso, Isabella Bernardis, Elena Tenedini, Lisa Pieri, Chiara Paoli, Carmela Mannarelli, Rajmonda Fjerza, Elisa Rumi, Viktoriya Stalbovskaya, Matthew Squires, Mario Cazzola, Rossella Manfredini, Claire Harrison, Enrico Tagliafico, Alessandro M Vannucchi
The JAK1/JAK2 inhibitor ruxolitinib produced significant reductions in splenomegaly and symptomatic burden and improved survival in patients with myelofibrosis (MF), irrespective of their JAK2 mutation status, in 2 phase III studies against placebo (COMFORT-I) and best available therapy (COMFORT-II). We performed a comprehensive mutation analysis to evaluate the impact of 14 MF-associated mutations on clinical outcomes in 166 patients included in COMFORT-II. We found that responses in splenomegaly and symptoms, as well as the risk of developing ruxolitinib-associated anemia and thrombocytopenia, occurred at similar frequencies across different mutation profiles...
April 3, 2014: Blood
https://www.readbyqxmd.com/read/24371211/impact-of-calreticulin-mutations-on-clinical-and-hematological-phenotype-and-outcome-in-essential-thrombocythemia
#6
Giada Rotunno, Carmela Mannarelli, Paola Guglielmelli, Annalisa Pacilli, Alessandro Pancrazzi, Lisa Pieri, Tiziana Fanelli, Alberto Bosi, Alessandro M Vannucchi
Mutations in the calreticulin (CALR) gene were recently discovered in patients with essential thrombocythemia (ET) lacking the JAK2V617F and MPLW515 mutations, but no information is available on the clinical correlates. In this series, CALR mutations were found in 15.5% of 576 World Health Organization-defined ET patients, accounting for 48.9% of JAK2 and MPL wild-type (wt) patients. CALR-mutated patients were preferentially male and showed higher platelet count and lower hemoglobin and leukocyte count compared with JAK2- and MPL-mutated patients...
March 6, 2014: Blood
https://www.readbyqxmd.com/read/24366362/jak2-or-calr-mutation-status-defines-subtypes-of-essential-thrombocythemia-with-substantially-different-clinical-course-and-outcomes
#7
Elisa Rumi, Daniela Pietra, Virginia Ferretti, Thorsten Klampfl, Ashot S Harutyunyan, Jelena D Milosevic, Nicole C C Them, Tiina Berg, Chiara Elena, Ilaria C Casetti, Chiara Milanesi, Emanuela Sant'antonio, Marta Bellini, Elena Fugazza, Maria C Renna, Emanuela Boveri, Cesare Astori, Cristiana Pascutto, Robert Kralovics, Mario Cazzola
Patients with essential thrombocythemia may carry JAK2 (V617F), an MPL substitution, or a calreticulin gene (CALR) mutation. We studied biologic and clinical features of essential thrombocythemia according to JAK2 or CALR mutation status and in relation to those of polycythemia vera. The mutant allele burden was lower in JAK2-mutated than in CALR-mutated essential thrombocythemia. Patients with JAK2 (V617F) were older, had a higher hemoglobin level and white blood cell count, and lower platelet count and serum erythropoietin than those with CALR mutation...
March 6, 2014: Blood
https://www.readbyqxmd.com/read/23575445/acquired-copy-neutral-loss-of-heterozygosity-of-chromosome-1p-as-a-molecular-event-associated-with-marrow-fibrosis-in-mpl-mutated-myeloproliferative-neoplasms
#8
Elisa Rumi, Daniela Pietra, Paola Guglielmelli, Roberta Bordoni, Ilaria Casetti, Chiara Milanesi, Emanuela Sant'Antonio, Virginia Ferretti, Alessandro Pancrazzi, Giada Rotunno, Marco Severgnini, Alessandro Pietrelli, Cesare Astori, Elena Fugazza, Cristiana Pascutto, Emanuela Boveri, Francesco Passamonti, Gianluca De Bellis, Alessandro Vannucchi, Mario Cazzola
We studied mutations of MPL exon 10 in patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF), first investigating a cohort of 892 consecutive patients. MPL mutation scanning was performed on granulocyte genomic DNA by using a high-resolution melt assay, and the mutant allele burden was evaluated by using deep sequencing. Somatic mutations of MPL, all but one involving codon W515, were detected in 26/661 (4%) patients with ET, 10/187 (5%) with PMF, and 7/44 (16%) patients with post-ET myelofibrosis...
May 23, 2013: Blood
https://www.readbyqxmd.com/read/23382981/mtor-inhibitors-alone-and-in-combination-with-jak2-inhibitors-effectively-inhibit-cells-of-myeloproliferative-neoplasms
#9
Costanza Bogani, Niccolò Bartalucci, Serena Martinelli, Lorenzo Tozzi, Paola Guglielmelli, Alberto Bosi, Alessandro M Vannucchi
BACKGROUND: Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN), usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis...
2013: PloS One
https://www.readbyqxmd.com/read/23160465/biologic-and-clinical-significance-of-somatic-mutations-of-sf3b1-in-myeloid-and-lymphoid-neoplasms
#10
REVIEW
Mario Cazzola, Marianna Rossi, Luca Malcovati
Precursor mRNA splicing is catalyzed by the spliceosome, a macromolecule composed of small nuclear RNAs associated with proteins. The SF3B1 gene encodes subunit 1 of the splicing factor 3b, which is important for anchoring the spliceosome to precursor mRNA. In 2011, whole-exome sequencing studies showed recurrent somatic mutations of SF3B1 and other genes of the RNA splicing machinery in patients with myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm. SF3B1 mutations had a particularly high frequency among conditions characterized by ring sideroblasts, which is consistent with a causal relationship...
January 10, 2013: Blood
https://www.readbyqxmd.com/read/23129323/spleen-endothelial-cells-from-patients-with-myelofibrosis-harbor-the-jak2v617f-mutation
#11
Vittorio Rosti, Laura Villani, Roberta Riboni, Valentina Poletto, Elisa Bonetti, Lorenzo Tozzi, Gaetano Bergamaschi, Paolo Catarsi, Elena Dallera, Francesca Novara, Margherita Massa, Rita Campanelli, Gabriela Fois, Benedetta Peruzzi, Marco Lucioni, Paola Guglielmelli, Alessandro Pancrazzi, Giacomo Fiandrino, Orsetta Zuffardi, Umberto Magrini, Marco Paulli, Alessandro M Vannucchi, Giovanni Barosi
Increased microvessel density contributes to abnormal BM and spleen microenvironment in myelofibrosis (MF). Taking advantage of the JAK2V617F mutation as a marker of malignancy, in the present study, we investigated whether splenic endothelial cells (ECs) obtained from capillaries by laser microdissection or from fresh spleen tissue by cell culture or cell sorting harbored such mutation in patients bearing the mutation in their granulocytes and undergoing splenectomy for therapeutical reasons. To extend the analysis to the ECs of large vessels, endothelial tissue from the splenic vein was also studied...
January 10, 2013: Blood
https://www.readbyqxmd.com/read/23111067/givinostat-and-hydroxyurea-synergize-in%C3%A2-vitro-to-induce-apoptosis-of-cells-from-jak2-v617f-myeloproliferative-neoplasm-patients
#12
Ariel Amaru Calzada, Olga Pedrini, Guido Finazzi, Flavio Leoni, Paolo Mascagni, Martino Introna, Alessandro Rambaldi, Josée Golay
We investigated whether clinically achievable concentrations of the histone deacetylase (HDAC) inhibitors givinostat and hydroxyurea induce synergistic cytotoxicity in Jak2(V617F) cells in vitro and through which possible mechanism. Givinostat and hydroxyurea at low doses potentiated the pro-apoptotic effects of each other in the Jak2(V617F) HEL and UKE1 cell lines. Givinostat induced 6.8%-20.8% and hydroxyurea (HU) 20.4%-42.4% cell death alone and 35.8%-75.3% in combination. The effect was statistically significant using the median effect Chou-Talalay method, resulting in a combination index less than 1, indicating synergy...
March 2013: Experimental Hematology
https://www.readbyqxmd.com/read/22223824/characterization-and-discovery-of-novel-mirnas-and-mornas-in-jak2v617f-mutated-set2-cells
#13
Stefania Bortoluzzi, Andrea Bisognin, Marta Biasiolo, Paola Guglielmelli, Flavia Biamonte, Ruggiero Norfo, Rossella Manfredini, Alessandro M Vannucchi et al.
To gain insights into a possible role of microRNAs in myeloproliferative neoplasms, we performed short RNA massive sequencing and extensive bioinformatic analysis in the JAK2V617F-mutated SET2 cell line. Overall, 652 known mature miRNAs were detected, of which 21 were highly expressed, thus being responsible of most of miRNA-mediated gene repression. microRNA putative targets were enriched in specific signaling pathways, providing information about cell activities under massive posttranscriptional regulation...
March 29, 2012: Blood
https://www.readbyqxmd.com/read/21998214/clinical-significance-of-sf3b1-mutations-in-myelodysplastic-syndromes-and-myelodysplastic-myeloproliferative-neoplasms
#14
MULTICENTER STUDY
Luca Malcovati, Elli Papaemmanuil, David T Bowen, Jacqueline Boultwood, Matteo G Della Porta, Cristiana Pascutto, Erica Travaglino, Michael J Groves, Anna L Godfrey, Ilaria Ambaglio, Anna Gallì, Matteo C Da Vià, Simona Conte, Sudhir Tauro, Norene Keenan, Ann Hyslop, Jonathan Hinton, Laura J Mudie, James S Wainscoat, P Andrew Futreal, Michael R Stratton, Peter J Campbell, Eva Hellström-Lindberg, Mario Cazzola
In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28...
December 8, 2011: Blood
https://www.readbyqxmd.com/read/21725052/safety-and-efficacy-of-everolimus-a-mtor-inhibitor-as-single-agent-in-a-phase-1-2-study-in-patients-with-myelofibrosis
#15
MULTICENTER STUDY
Paola Guglielmelli, Giovanni Barosi, Alessandro Rambaldi, Roberto Marchioli, Arianna Masciulli, Lorenzo Tozzi, Flavia Biamonte, Niccolò Bartalucci, Elisabetta Gattoni, Maria Letizia Lupo, Guido Finazzi, Alessandro Pancrazzi, Elisabetta Antonioli, Maria Chiara Susini, Lisa Pieri, Elisa Malevolti, Emilio Usala, Ubaldo Occhini, Alberto Grossi, Silvia Caglio, Simona Paratore, Alberto Bosi, Tiziano Barbui, Alessandro M Vannucchi
In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis, a myeloproliferative neoplasm with no approved therapies. We conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high- or intermediate-risk primary or postpolycythemia vera/postessential thrombocythemia myelofibrosis subjects. Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in phase 1 up to 10 mg/d. When this dose was used in phase 2, grade ≥ 3 toxicities were infrequent; the commonest toxicity was grade 1-2 stomatitis...
August 25, 2011: Blood
https://www.readbyqxmd.com/read/21591355/-implementation-of-direct-sequencing-as-a-method-of-abl-gene-mutations-analysis-in-patients-with-chronic-myeloid-leukemia-treated-with-tyrosine-kinase-inhibitor
#16
Izabela Florek, Tomasz Sacha, Magdalena Zawada, Sylwia Czekalska, Kajetana Foryciarz, Dorota Cwynar, Elzbieta Pecek, Aleksander B Skotnicki
Chronic Myeloid Leukemia (CML), belonging to mieloproliferative syndromes, is one of the myeloproliferative clonal hyperplasia. It is caused by the Philadelphia chromosome resulting from the reciprocal translocation, t(9;22) between the long arms of chromosomes 9 and 22. This results in the production of fusion BCR-ABL transcript and chimeric protein--tyrosine kinase activity. This protein leads to increased proliferation, resistance to apoptosis, and worse adhesion of CML cells. Molecular analysis are very important in the era treatment of CML by tyrosine kinase inhibitors (TKI)...
2010: Przegla̧d Lekarski
https://www.readbyqxmd.com/read/21527532/overexpression-of-microrna-16-2-contributes-to-the-abnormal-erythropoiesis-in-polycythemia-vera
#17
Paola Guglielmelli, Lorenzo Tozzi, Costanza Bogani, Ilaria Iacobucci, Vanessa Ponziani, Giovanni Martinelli, Alberto Bosi, Alessandro M Vannucchi et al.
Deregulated expression of microRNAs is associated with neoplasia. Here, we show that mature miR-16 levels are abnormally increased in CD34(+) cells of patients with polycythemia vera as a consequence of preferential expression of miR-16-2 on chromosome 3 rather than of miR-16-1 on chromosome 13. Forced expression of miRNA-16 in normal CD34(+) cells stimulated erythroid cell proliferation and maturation. Conversely, exposure of polycythemia vera CD34(+) cells to small interfering RNA against pre-miR-16-2 reduced erythroid colonies and largely prevented formation of erythropoietin-independent colonies; myeloid progenitors remained unaffected...
June 23, 2011: Blood
https://www.readbyqxmd.com/read/10800165/diagnosis-of-essential-thrombocythemia-at-platelet-counts-between-400-and-600x10-9-l-gruppo-italiano-malattie-mieloproliferative-croniche-gimmc
#18
S Sacchi, G Vinci, L Gugliotta, S Rupoli, L Gargantini, V Martinelli, S Baravelli, M Lazzarino, G Finazzi
BACKGROUND AND OBJECTIVE: Diagnostic criteria for essential thrombocythemia (ET) remain essentially negative, that is, exclusion of other myeloproliferative diseases and causes of reactive thrombocytosis. A platelet count above 600x10(9)/L is still generally considered an absolute diagnostic criterion although new protocols for positive diagnostic criteria have recently been proposed, reducing the stringency of a definite platelet limit. This study demonstrates that a platelet count 600x10(9)/L is not a reliable diagnostic criterion for ET, especially in the early stages...
May 2000: Haematologica
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