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Dive into the research topics where Tiziana Fanelli is active.

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Featured researches published by Tiziana Fanelli.


Blood | 2014

Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia.

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. Patients carrying the CALR mutation had a lower risk of thrombosis than JAK2- and MPL-mutated patients; of interest, their risk was superimposable to patients who were wt for the above mutations. CALR mutation had no impact on survival or transformation to post-ET myelofibrosis. Genotyping for CALR mutations represents a novel useful tool for establishing a clonal myeloproliferative disorder in JAK2 and MPL wt patients with thrombocytosis and may have prognostic and therapeutic relevance.


Blood | 2011

EZH2 mutational status predicts poor survival in myelofibrosis.

Paola Guglielmelli; Flavia Biamonte; Joannah Score; Claire Hidalgo-Curtis; Francisco Cervantes; Margherita Maffioli; Tiziana Fanelli; Thomas Ernst; Nils Winkelman; Amy V. Jones; Katerina Zoi; Andreas Reiter; Andrew S Duncombe; Laura Villani; Alberto Bosi; Giovanni Barosi; Nicholas C.P. Cross; Alessandro M. Vannucchi

We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. EZH2 mutation coexisted with JAK2V617F or ASXL1 mutation in 12 of 29 (41.4%) and 6 of 27 (22.2%) evaluated patients; TET2 and CBL mutations were found in 2 and 1 patients, respectively. EZH2-mutated PMF patients had significantly higher leukocyte counts, blast-cell counts, and larger spleens at diagnosis, and most of them (52.6%) were in the high-risk International Prognostic Score System (IPSS) category. After a median follow-up of 39 months, 128 patients (25.9%) died, 81 (63.3%) because of leukemia. Leukemia-free survival (LFS) and overall survival (OS) were significantly reduced in EZH2-mutated PMF patients (P = .028 and P < .001, respectively); no such impact was seen for PPV/PET-MF patients, possibly due to the low number of mutated cases. In multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZH2 mutation status. We conclude that EZH2 mutations are independently associated with shorter survival in patients with PMF.


Leukemia | 2014

The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients

Paola Guglielmelli; Terra L. Lasho; Giada Rotunno; Joannah Score; Carmela Mannarelli; Alessandro Pancrazzi; Flavia Biamonte; Animesh Pardanani; Katerina Zoi; Andreas Reiter; Andrew S Duncombe; Tiziana Fanelli; Daniela Pietra; Elisa Rumi; Christy Finke; Naseema Gangat; Rhett P. Ketterling; Ryan A. Knudson; Curt A. Hanson; Alberto Bosi; Arturo Pereira; Rossella Manfredini; Francisco Cervantes; Giovanni Barosi; Marie Cazzola; Nicholas C.P. Cross; Alessandro M. Vannucchi; Ayalew Tefferi

We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of the five ‘prognostically detrimental’ mutated genes (ASXL1, EZH2, SRSF2 and IDH1/2). Herein, we evaluate the additional prognostic value of the ‘number’ of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had two or more mutated genes. The presence of two or more mutations predicted the worst survival: median 2.6 years (hazard ratio (HR) 3.8, 95% confidence interval (CI) 2.6–5.7) vs 7.0 years (HR 1.9, 95% CI 1.4–2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of International Prognostic Scoring System (IPSS; HR 2.4, 95% CI 1.6–3.6) and dynamic IPSS (DIPSS)-plus (HR 1.9, 95% CI 1.2–3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5–10.7), also Mayo validated. Calreticulin mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the ‘number’ of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF.


Blood | 2014

miRNA-mRNA integrative analysis in primary myelofibrosis CD34+ cells: role of miR-155/JARID2 axis in abnormal megakaryopoiesis

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. By means of miRNA-gene expression integrative analysis, we found different regulatory networks involved in the dysregulation of transcriptional control and chromatin remodeling. In particular, we identified a network gathering several miRNAs with oncogenic potential (eg, miR-155-5p) and targeted genes whose abnormal function has been previously associated with myeloid neoplasms, including JARID2, NR4A3, CDC42, and HMGB3. Because the validation of miRNA-target interactions unveiled JARID2/miR-155-5p as the strongest relationship in the network, we studied the function of this axis in normal and PMF CD34(+) cells. We showed that JARID2 downregulation mediated by miR-155-5p overexpression leads to increased in vitro formation of CD41(+) MK precursors. These findings suggest that overexpression of miR-155-5p and the resulting downregulation of JARID2 may contribute to MK hyperplasia in PMF.


Leukemia | 2014

Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms

Elena Tenedini; Isabella Bernardis; Valentina Artusi; Lucia Artuso; Enrica Roncaglia; Paola Guglielmelli; Lisa Pieri; Costanza Bogani; Flavia Biamonte; Giada Rotunno; Carmela Mannarelli; Elisa Bianchi; Alessandro Pancrazzi; Tiziana Fanelli; G Malagoli Tagliazucchi; Sergio Ferrari; Rossella Manfredini; Alessandro M. Vannucchi; Enrico Tagliafico

With the intent of dissecting the molecular complexity of Philadelphia-negative myeloproliferative neoplasms (MPN), we designed a target enrichment panel to explore, using next-generation sequencing (NGS), the mutational status of an extensive list of 2000 cancer-associated genes and microRNAs. The genomic DNA of granulocytes and in vitro-expanded CD3+T-lymphocytes, as a germline control, was target-enriched and sequenced in a learning cohort of 20 MPN patients using Roche 454 technology. We identified 141 genuine somatic mutations, most of which were not previously described. To test the frequency of the identified variants, a larger validation cohort of 189 MPN patients was additionally screened for these mutations using Ion Torrent AmpliSeq NGS. Excluding the genes already described in MPN, for 8 genes (SCRIB, MIR662, BARD1, TCF12, FAT4, DAP3, POLG and NRAS), we demonstrated a mutation frequency between 3 and 8%. We also found that mutations at codon 12 of NRAS (NRASG12V and NRASG12D) were significantly associated, for primary myelofibrosis (PMF), with highest dynamic international prognostic scoring system (DIPSS)-plus score categories. This association was then confirmed in 66 additional PMF patients composing a final dataset of 168 PMF showing a NRAS mutation frequency of 4.7%, which was associated with a worse outcome, as defined by the DIPSS plus score.


Blood Cancer Journal | 2015

Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis

Paola Guglielmelli; Giada Rotunno; Tiziana Fanelli; Annalisa Pacilli; G Brogi; Laura Calabresi; Alessandro Pancrazzi; Alessandro M. Vannucchi

The discovery of mutations in calreticulin (CALR) in patients with primary myelofibrosis (PMF)1, 2 prompted a reappraisal of the clinical correlates and prognostic impact of the so-called driver mutations that include JAK2V617F, MPLW515L/K/A and CALR in ~60%, 5–10% and 20–25% of patients, respectively. As compared with their JAK2V617F counterpart, PMF patients harboring CALR mutations showed younger age, higher platelet and lower hemoglobin and leukocyte counts. The cumulative incidence of anemia, leukocytosis and thrombocytopenia was significantly lower in CALR-mutated patients who were also less likely to be red cell transfusion-dependent;3, 4 in addition, they had significantly longer large splenomegaly-free survival compared with the other genotypes as well as patients lacking the three driver mutations (triple-negative (TN) patients).3, 4 Interestingly, spliceosome mutations were significantly less represented in CALR-mutated patients; however, no additional molecular or cytogenetic correlate was highlighted.3 These data suggested a milder disease in patients harboring the CALR mutation, and conceivably the presence of CALR mutation was associated with better overall survival (OS) when compared with JAK2V617F- and MPLW515-mutated patients, and particularly TN patients.3, 4 In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of International Prognostic Scoring System (IPSS), Dinamic IPSS (DIPSS)4 or DIPSS-plus risk stratification,3 and also of ASXL1 mutation, known for its dismal impact on survival in PMF.5 At this regard, we found that DIPSS-plus-independent OS was significantly longer in CALR-mutated/ASXL1-unmutated compared with CALR-unmutated/ASXL1-mutated patients.6


American Journal of Hematology | 2016

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group.

Giada Rotunno; Annalisa Pacilli; Valentina Artusi; Elisa Rumi; Margherita Maffioli; Federica Delaini; Giada Brogi; Tiziana Fanelli; Alessandro Pancrazzi; Daniela Pietra; Isabella Bernardis; Clara Belotti; Lisa Pieri; Emanuela Sant'Antonio; Silvia Salmoiraghi; Daniela Cilloni; Alessandro Rambaldi; Francesco Passamonti; Tiziano Barbui; Rossella Manfredini; Mario Cazzola; Enrico Tagliafico; Alessandro M. Vannucchi; Paola Guglielmelli

Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PPV‐MF) and essential thrombocythemia (PET‐MF). Although primary (PMF) and secondary MF are considered similar diseases and managed similarly, there are few studies specifically focused on the latter. The aim of this study was to characterize the mutation landscape, and describe the main clinical correlates and prognostic implications of mutations, in a series of 359 patients with PPV‐MF and PET‐MF. Compared with PV and ET, the JAK2V617F and CALR mutated allele burden was significantly higher in PPV‐MF and/or PET‐MF, indicating a role for accumulation of mutated alleles in the process of transformation to MF. However, neither the allele burden nor the type of driver mutation influenced overall survival (OS), while absence of any driver mutation (triple negativity) was associated with significant reduction of OS in PET‐MF, similar to PMF. Of the five interrogated subclonal mutations (ASXL1, EZH2, SRSF2, IDH1, and IDH2), that comprise a prognostically detrimental high molecular risk (HMR) category in PMF, only SRSF2 mutations were associated with reduced survival in PET‐MF, and no additional mutation profile with prognostic relevance was highlighted. Overall, these data indicate that the molecular landscape of secondary forms of MF is different from PMF, suggesting that unknown mutational events might contribute to the progression from chronic phase disease to myelofibrosis. These findings also support more extended genotyping approaches aimed at identifying novel molecular abnormalities with prognostic relevance for patients with PPV‐MF and PET‐MF. Am. J. Hematol. 91:681–686, 2016.


Blood | 2015

JAK2V617F complete molecular remission in polycythemia vera/essential thrombocythemia patients treated with ruxolitinib

Lisa Pieri; Alessandro Pancrazzi; Annalisa Pacilli; Claudia Rabuzzi; Giada Rotunno; Tiziana Fanelli; Paola Guglielmelli; Rajmonda Fjerza; Chiara Paoli; Srdan Verstovsek; Alessandro M. Vannucchi

To the editor: Polycythemia vera (PV) and essential thrombocythemia (ET) are characterized by JAK2 V617F mutation in 95% and 60% of the patients, respectively.[1][1] Ruxolitinib is a JAK1/JAK2 inhibitor approved for myelofibrosis (MF) and more recently for hydroxyurea resistant/intolerant PV


American Journal of Hematology | 2016

Prognostic Impact of Bone Marrow Fibrosis in Primary Myelofibrosis. A Study of the AGIMM Group on 490 Patients

Paola Guglielmelli; Giada Rotunno; Annalisa Pacilli; Elisa Rumi; Vittorio Rosti; Federica Delaini; Margherita Maffioli; Tiziana Fanelli; Alessandro Pancrazzi; Lisa Pieri; Rajmonda Fjerza; Daniela Pietra; Daniela Cilloni; Emanuela Sant'Antonio; Silvia Salmoiraghi; Francesco Passamonti; Alessandro Rambaldi; Giovanni Barosi; Tiziano Barbui; Mario Cazzola; Alessandro M. Vannucchi

The prognostic significance of bone marrow (BM) fibrosis grade in patients with primary myelofibrosis (PMF) is still debated. A fibrosis grade greater than 1 was shown to associate with higher risk of death, and addition of fibrosis grade to IPSS score resulted in a more accurate prediction of survival. The aim of this study was to analyze the prognostic impact of BM fibrosis in 490 patients with PMF, evaluated at diagnosis, molecularly annotated and with extensive follow‐up information. We found that fibrosis grade 2 and greater on a 0–3 scale was associated with clinical characteristics indicative of a more advanced disease, such as anemia, leukopenia, thrombocytopenia, constitutional symptoms, larger splenomegaly and a higher IPSS risk category. Patients with higher grade of fibrosis were also more likely to have additional somatic mutations in ASXL1 and EZH2, that are prognostically adverse. Median survival was significantly reduced in patients with grade 2 and 3 fibrosis as compared with grade 1; this effect was maintained when analysis was restricted to younger patients. In multivariate analysis, fibrosis grade independently predicted for survival regardless of IPSS variables and mutational status; the adverse impact of fibrosis was noticeable especially in lower IPSS risk categories. Overall, results indicate that higher grades of fibrosis correlate with unique clinical and molecular aspects and represent an independent adverse variable in patients with PMF; these observations deserve confirmation in prospectively designed series of patients. Am. J. Hematol. 91:918–922, 2016.


Haematologica | 2013

Infrequent occurrence of mutations in the PH domain of LNK in patients with JAK2 mutation-negative "idiopathic" erythrocytosis

Ambra Spolverini; Lisa Pieri; Paola Guglielmelli; Alessandro Pancrazzi; Tiziana Fanelli; Chiara Paoli; Alberto Bosi; Ilaria Nichele; Marco Ruggeri; Alessandro M. Vannucchi

LNK (SH2B3) belongs to a family of adaptor proteins that contain a proline-rich N-terminal dimerization domain, a pleckstrin homology domain (PH), an Src homology-2 domain (SH2), and a conserved C-terminal tyrosine residue. By binding to cytokine receptors and JAK2 through the SH2 domain, LNK

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Lisa Pieri

University of Florence

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Rossella Manfredini

University of Modena and Reggio Emilia

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