scholarly journals The Role of Neutrophilic Granulocytes in Philadelphia Chromosome Negative Myeloproliferative Neoplasms

2021 ◽  
Vol 22 (17) ◽  
pp. 9555
Author(s):  
Dominik Kiem ◽  
Sandro Wagner ◽  
Teresa Magnes ◽  
Alexander Egle ◽  
Richard Greil ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Myeloid Cell ◽  
Primary Myelofibrosis ◽  
Neutrophilic Granulocytes ◽  
Essential Thrombocytosis ◽  
Cell Lineages ◽  
Hemorrhagic Events ◽  
Venous Thromboembolic

Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are composed of polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The clinical picture is determined by constitutional symptoms and complications, including arterial and venous thromboembolic or hemorrhagic events. MPNs are characterized by mutations in JAK2, MPL, or CALR, with additional mutations leading to an expansion of myeloid cell lineages and, in PMF, to marrow fibrosis and cytopenias. Chronic inflammation impacting the initiation and expansion of disease in a major way has been described. Neutrophilic granulocytes play a major role in the pathogenesis of thromboembolic events via the secretion of inflammatory markers, as well as via interaction with thrombocytes and the endothelium. In this review, we discuss the molecular biology underlying myeloproliferative neoplasms and point out the central role of leukocytosis and, specifically, neutrophilic granulocytes in this group of disorders.

Leukaemic Transformation of Philadelphia-chromosome-negative Myeloproliferative Neoplasms — A Review of the Molecular Background

2011 ◽  
Vol 07 (01) ◽  
pp. 59
Author(s):  
Nils H Thoennissen ◽  
H Phillip Koeffler ◽  
◽  
Keyword(s):  
Chromosomal Abnormalities ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myeloid Cell ◽  
Primary Myelofibrosis ◽  
Haematopoietic Stem Cell ◽  
Polycythaemia Vera ◽  
Causative Role ◽  
Blast Phase

Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), including polycythaemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythaemia (ET), are clonal haematopoietic stem cell disorders characterised by proliferation of one or more myeloid cell lineages. They are closely associated with theJAK2V617F mutation, whose detection is used as a clonal marker in the differential diagnosis of MPN. Despite recent improvements in the molecular diagnosis and therapeutic regimen of these chronic disorders, haematological evolution to blast phase remains a major cause of long-term mortality. The mechanism of MPN transformation is still a matter of some controversy because of insufficient insights into the underlying molecular pathogenesis. The purpose of this article is to summarise the increasing data concerning the mechanism of leukaemic evolution of patients diagnosed with chronic MPN. Chromosomal abnormalities and genes that have been shown to play a potential causative role in chronic-phase acceleration are discussed, as are aberrations that may serve as prognostic markers in the blast phase of MPN.

Oxford Specialist Handbook: Myeloproliferative Neoplasms

2020 ◽  
Keyword(s):  
State Of The Art ◽  
Myeloproliferative Neoplasms ◽  
Myeloid Cell ◽  
Primary Myelofibrosis ◽  
Polycythaemia Vera ◽  
Clinical Knowledge ◽  
Cell Lineages ◽  
The Past ◽  
Accessible Format ◽  
Excessive Accumulation

Our understanding of myeloproliferative neoplasms (MPN) disorders, a group of clonal haematological malignancies characterized by excessive accumulation of one or more myeloid cell lineages, has grown considerably over the past four decades. Even more importantly is the speed at which many of these findings were translated to accord survival benefits to our patients with MPN, in particular chronic myeloid leukaemia (CML), polycythaemia vera (PV), essential thrombocythaemia (ET), and primary myelofibrosis (PMF). This text offers a detailed evidence-based guide to MPN in an easily accessible format, structure to facilitate learning specialist information presenting core information in ‘bite size’ chunks. Each chapter summarizes the state-of-the art preclinical and clinical knowledge, and its impact on the clinical management of patients with MPN.

scholarly journals Experimental Modeling of Myeloproliferative Neoplasms

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 813 ◽  
Author(s):  
Lucie Lanikova ◽  
Olga Babosova ◽  
Josef T. Prchal
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Drug Efficacy ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Essential Thrombocytosis ◽  
Oncogenic Signaling ◽  
Novel Technologies ◽  
Genetic Landscape ◽  
Induced Pluripotent

Myeloproliferative neoplasms (MPN) are genetically very complex and heterogeneous diseases in which the acquisition of a somatic driver mutation triggers three main myeloid cytokine receptors, and phenotypically expresses as polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The course of the diseases may be influenced by germline predispositions, modifying mutations, their order of acquisition and environmental factors such as aging and inflammation. Deciphering these contributory elements, their mutual interrelationships, and their contribution to MPN pathogenesis brings important insights into the diseases. Animal models (mainly mouse and zebrafish) have already significantly contributed to understanding the role of several acquired and germline mutations in MPN oncogenic signaling. Novel technologies such as induced pluripotent stem cells (iPSCs) and precise genome editing (using CRISPR/Cas9) contribute to the emerging understanding of MPN pathogenesis and clonal architecture, and form a convenient platform for evaluating drug efficacy. In this overview, the genetic landscape of MPN is briefly described, with an attempt to cover the main discoveries of the last 15 years. Mouse and zebrafish models of the driver mutations are discussed and followed by a review of recent progress in modeling MPN with patient-derived iPSCs and CRISPR/Cas9 gene editing.

Loss of Wild-Type Jak2 Allele Enhances Myeloid Cell Expansion and Accelerates Myelofibrosis in Jak2V617F Knock-in Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 809-809
Author(s):  
Hajime Akada ◽  
Saeko Akada ◽  
Dongqing Yan ◽  
Robert Hutchison ◽  
Golam Mohi
Keyword(s):  
Polycythemia Vera ◽  
Cell Expansion ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Myeloid Cell ◽  
Negative Regulator ◽  
Jak2v617f Mutation ◽  
Common Mutation ◽  
Wild Type

Abstract Abstract 809 The activating JAK2V617F mutation is the most common mutation found in Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs), which include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p involving JAK2 has been observed in ∼30% of patients with MPNs particularly in PV and PMF. JAK2V617F homozygosity through 9pLOH has been linked to more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the role of wild-type JAK2 in MPNs induced by JAK2V617F, we have utilized conditional Jak2 knock-out and Jak2V617F knock-in alleles and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like disease in mice, loss of wild-type Jak2 allele in hemizygous or homozygous Jak2V617F mice results in a significantly greater increase in reticulocytes, white blood cells, neutrophils and platelets in the peripheral blood and larger spleen size. We also have found that hemizygous or homozygous Jak2V617F expression significantly increased megakaryocyte-erythroid progenitors in the bone marrow and spleens and marked infiltration of neutrophils in the liver compared with heterozygous Jak2V617F. More importantly, hemizygous or homozygous Jak2V617F mice show accelerated myelofibrosis compared with heterozygous Jak2V617F-expressing mice. Thus, loss of wild type Jak2 allele increases myeloid cell expansion and enhances the severity of the MPN. Together, these results suggest that wild-type Jak2 serves as a negative regulator of MPN induced by Jak2V617F. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera–like disease

Blood ◽  
2010 ◽  
Vol 115 (17) ◽  
pp. 3589-3597 ◽  
Author(s):  
Hajime Akada ◽  
Dongqing Yan ◽  
Haiying Zou ◽  
Steven Fiering ◽  
Robert E. Hutchison ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Gene Dosage ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Erythroid Progenitors ◽  
Conditional Expression ◽  
Biochemical Analyses ◽  
Genetic Events ◽  
Serum Erythropoietin

Abstract A somatic point mutation (V617F) in the JAK2 tyrosine kinase was found in a majority of patients with polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. However, contribution of the JAK2V617F mutation in these 3 clinically distinct myeloproliferative neoplasms (MPNs) remained unclear. To investigate the role of JAK2V617F in the pathogenesis of these MPNs, we generated an inducible Jak2V617F knock-in mouse, in which the expression of Jak2V617F is under control of the endogenous Jak2 promoter. Expression of heterozygous mouse Jak2V617F evoked all major features of human polycythemia vera (PV), which included marked increase in hemoglobin and hematocrit, increased red blood cells, leukocytosis, thrombocytosis, splenomegaly, reduced serum erythropoietin (Epo) levels and Epo-independent erythroid colonies. Homozygous Jak2V617F expression also resulted in a PV-like disease associated with significantly greater reticulocytosis, leukocytosis, neutrophilia and thrombocytosis, marked expansion of erythroid progenitors and Epo-independent erythroid colonies, larger spleen size, and accelerated bone marrow fibrosis compared with heterozygous Jak2V617F expression. Biochemical analyses revealed Jak2V617F gene dosage-dependent activation of Stat5, Akt, and Erk signaling pathways. Our conditional Jak2V617F knock-in mice provide an excellent model that can be used to further understand the molecular pathogenesis of MPNs and to identify additional genetic events that cooperate with Jak2V617F in different MPNs.

scholarly journals RMC-4550, an Allosteric Inhibitor of SHP2, Displays Therapeutic Efficacy in Pre-Clinical Models of Myeloproliferative Neoplasms

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4198-4198 ◽  
Author(s):  
Garima Pandey ◽  
Nathan Horvat ◽  
Narmin E. Amin ◽  
Afua A. Akuffo ◽  
Christelle Colin ◽  
...  
Keyword(s):  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Critical Role ◽  
Philadelphia Chromosome ◽  
Jak2 V617f ◽  
Ras Signaling ◽  
Jak2 Inhibitor ◽  
Stat Signaling ◽  
Drug Naïve

Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are JAK2-driven disorders resulting from mutations in JAK2, MPL, or CALR. Ruxolitinib, the only FDA-approved JAK2 inhibitor for MPNs, alleviates patient symptomology and improves quality of life, but has little effect on reducing mutant allele burden. This persistent survival of MPN cells in the face of ruxolitinib, as well as other JAK2 inhibitors that have been clinically tested, is a major clinical bottleneck to the development of an effective targeted therapy for MPN patients. Identifying new therapeutic targets which play critical roles in MPN cells and/or in JAK2 inhibitor persistence may lead to improved MPN therapies. SHP2 is an oncogenic tyrosine phosphatase that is an effector of growth factor and cytokine receptor signaling. SHP2 plays a critical role in the activation of the RAS-ERK pathway and regulates JAK-STAT signaling via numerous phosphatase-dependent mechanisms. Activating mutations of SHP2(PTPN11) have been identified in leukemia, including 8% of MPN patients whose disease progressed to acute myeloid leukemia (AML). In addition, SHP2 has been shown to mediate adaptive resistance to targeted therapies in several cancers. Given the role of SHP2 in cytokine and JAK-STAT signaling, we envisaged a potential role of SHP2 in MPN cell growth and/or survival and ruxolitinib persistence. Treatment of JAK2-V617F-driven MPN model cell lines (UKE1, SET2, and BaF3-JAK2-V617F) with ruxolitinib blocked constitutive tyrosine phosphorylation of SHP2, including phosphorylation of Y542, a marker for activated SHP2. This phosphorylation, however, was restored in ruxolitinib persistent cells. Combination treatment of the allosteric SHP2 inhibitor RMC-4550 (Revolution Medicines) with ruxolitinib prevented the development of ruxolitinib persistent cells and pre-established persistent cells remained sensitive to SHP2 inhibition. RMC-4550 treatment led to significantly reduced levels of pERK consistent with the role of SHP2 in RAS signaling. Interestingly, pERK levels in persistent cells were more sensitive to SHP2 inhibition compared to drug naïve cells suggesting pERK was more dependent on SHP2 in ruxolitinib persistent cells. SHP2 inhibitor treatment increased pSTAT5(Y694) in drug naïve cells but this increase was not observed in similarly treated persistent cells. Furthermore, while ruxolitinib inhibited pERK levels in UKE1 and SET2 cells, pERK levels recovered within 24 hrs of treatment. SHP2 inhibition prevented the recovery of pERK in the presence of ruxolitinib. Collectively, these data suggest that signaling pathways in MPN cells treated with ruxolitinib can become rewired, gaining greater dependence on SHP2, concomitant with sustained pERK and cell survival/growth. Interestingly, we identified a known activating SHP2 mutation (F71L) in UKE1 cells obtained from two independent sources - consistent with the presence of PTPN11 mutations in post-MPN AML. The persistent survival of UKE1 cells in ruxolitinib was antagonized by CRISPR-mediated reduction of SHP2 expression, providing further evidence that SHP2 contributes to ruxolitinib persistence. To assess the effects of a SHP2 inhibitor on MPN progression in vivo, we employed the MPLW515Lbone marrow transplant mouse model of MPN. Initial assessment of therapeutic treatment of mice with an established MPN phenotype indicated that once daily treatment of RMC-4550 (10 or 30 mg/kg) antagonized the MPN phenotype. Complete blood counts indicated a significant reduction in white blood cells, monocytes, and neutrophils compared to vehicle treated mice, while flow cytometry analysis indicated RMC-4550 diminished CD11b+ cell numbers to near that observed in mice transplanted with MPLWT-transduced bone marrow. RMC-4550 improved the overall health of diseased mice, as indicated by increased weight, and significantly reduced organomegaly of the spleen and liver compared to vehicle treated MPN mice. Finally, erythropoietin independent erythroid colony formation of JAK2V617F-positive MPN patient cells was suppressed following SHP2 inhibition, which synergized or enhanced the inhibition induced by ruxolitinib in this assay. In summary, our results suggest that SHP2 inhibition may represent a potential MPN therapy in both ruxolitinib naïve and resistant patients and is an attractive therapeutic target for future clinical investigation. Disclosures Epling-Burnette: Incyte Corporation: Research Funding; Forma Therapeutics: Research Funding; Celgene Corporation: Patents & Royalties, Research Funding. Reuther:Incyte Corporation: Research Funding.

scholarly journals Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53

2018 ◽  
Vol 2 (24) ◽  
pp. 3581-3589 ◽  
Author(s):  
Bridget K. Marcellino ◽  
Ronald Hoffman ◽  
Joseph Tripodi ◽  
Min Lu ◽  
Heidi Kosiorek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Chromosomal Abnormalities ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Primary Myelofibrosis ◽  
Chromosome 17 ◽  
Transcript Levels ◽  
History Of ◽  
Tumor Protein P53

Abstract The Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (PMF), frequently progress to more overt forms of MF and a type of acute leukemia termed MPN-accelerated phase/blast phase (MPN-AP/BP). Recent evidence indicates that dysregulation of the tumor suppressor tumor protein p53 (TP53) commonly occurs in the MPNs. The proteins MDM2 and MDM4 alter the cellular levels of TP53. We investigated in 1,294 patients whether abnormalities involving chromosomes 1 and 12, which harbor the genes for MDM4 and MDM2, respectively, and chromosome 17, where the gene for TP53 is located, are associated with MPN disease progression. Gain of 1q occurred not only in individuals with MPN-BP but also in patients with PV and ET, who, with further follow-up, eventually evolve to either MF and/or MPN-BP. These gains of 1q were most prevalent in patients with a history of PV and those who possessed the JAK2V617F driver mutation. The gains of 1q were accompanied by increased transcript levels of MDM4. In contrast, 12q chromosomal abnormalities were exclusively detected in patients who presented with MF or MPN-BP, but were not accompanied by further increases in MDM2/MDM4 transcript levels. Furthermore, all patients with a loss of 17p13, which leads to a deletion of TP53, had either MF or MPN-AP/BP. These findings suggest that gain of 1q, as well as deletions of 17p, are associated with perturbations of the TP53 pathway, which contribute to MPN disease progression.

scholarly journals Genomics of Myeloproliferative Neoplasms

2017 ◽  
Vol 35 (9) ◽  
pp. 947-954 ◽  
Author(s):  
Katerina Zoi ◽  
Nicholas C.P. Cross
Keyword(s):  
Clinical Laboratory ◽  
Myeloproliferative Neoplasms ◽  
Genomic Analysis ◽  
Myeloid Cell ◽  
Scoring Systems ◽  
Driver Mutations ◽  
Cell Lineages ◽  
Disease Definition ◽  
Genetic Complexity ◽  
Multiple Abnormalities

Myeloproliferative neoplasms (MPNs) are a group of related clonal hematologic disorders characterized by excess accumulation of one or more myeloid cell lineages and a tendency to transform to acute myeloid leukemia. Deregulated JAK2 signaling has emerged as the central phenotypic driver of BCR -ABL1–negative MPNs and a unifying therapeutic target. In addition, MPNs show unexpected layers of genetic complexity, with multiple abnormalities associated with disease progression, interactions between inherited factors and phenotype driver mutations, and effects related to the order in which mutations are acquired. Although morphology and clinical laboratory analysis continue to play an important role in defining these conditions, genomic analysis is providing a platform for better disease definition, more accurate diagnosis, direction of therapy, and refined prognostication. There is an emerging consensus with regard to many prognostic factors, but there is a clear need to synthesize genomic findings into robust, clinically actionable and widely accepted scoring systems as well as the need to standardize the laboratory methodologies that are used.

The Clinical Phenotype of Patients with Primary Myelofibrosis, Polycythemia Vera, and Essential Thrombocytosis Whom Only Manifest WHO Grade 1 Fibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3208-3208
Author(s):  
Krisstina L. Gowin ◽  
Amylou Constance Dueck ◽  
Srdan Verstovsek ◽  
Naval Daver ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Diagnostic Criteria ◽  
Clinical Characteristics ◽  
Clinical Phenotype ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Population Characteristics ◽  
Essential Thrombocytosis ◽  
Who Grade ◽  
Marrow Fibrosis

Abstract Introduction: The clinical phenotype of patients with myeloproliferative neoplasms (MPNs) including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET) who manifest WHO grade 1 (on a 0-3 scale) for intramedullary fibrosis is poorly defined, and may represent MPN patients in a transitional state. We have specifically observed patients with existing PV and ET who manifest clinical progression towards a post PV/ET phenotype (IWG-MRT criteria) yet fail to progress to a 2+ marrow fibrosis. In contrast, the 2008 WHO definition of PMF does not require a minimum fibrosis threshold as long as patients meet the diagnostic criteria. In this study, we retrospectively analyzed the clinical characteristics and outcomes of MPN patients with 1+ marrow fibrosis. Methods: MPN patients with WHO grade 1 (scale 0-3) fibrosis within two institutional databases were identified. The clinical characteristics, laboratory, and outcome data were collected. Data were compared between PMF and PV/ET patients. 2008 IWG-MRT criteria were applied to PV/ET patients with exclusion of fibrosis component. Results: 91 MPN patients with WHO grade 1 fibrosis were identified, PMF in 33 patients (36%), PV in 37 (41%), ET in 20 (22%), and MPN-U in 1 (1%). The population characteristics are reported in Table 1. The majority (56%) of patients exhibited one or more symptoms (weight loss, night sweats, early satiety, bone pain, fatigue). The presence of symptomatic disease was similar between groups, with 52% PMF versus 57% PV/ET exhibiting at least one symptom. Symptoms were more severe in the PMF group with DIPSS risk of intermediate 2 or higher being present in 39%(PMF) versus 29% (PV/ET). Erythrocyte transfusion dependence occurred in a small percentage of overall population (9%), and was seen primarily in the PMF group (6/8 patients). Incidence and severity of splenomegaly was higher in the PMF group, with 55% having splenomegaly versus 43% of the PV/ET group. A higher incidence of a leukoerythoblastic blood smears was seen in PMF (45%) than PV/ET (38%). Two or more prior medical therapies were utilized in 45/90 (49%) of patients, with the most common prior therapies including hydroxyurea (71%), pegylated interferon (28%), anagrelide (18%), Jak inhibitor (13%), lenalidomide (4%), and prednisone (4%). At the time of this analysis, 78/91 patients (86%) were alive. When IWG-MRT criteria were applied to the PV/ET group, 38/58 (66%) of patients fulfilled criteria for diagnosis of post-PV/ET myelofibrosis (except for the 2+fibrosis requirement). Table 1 Patient characteristics UPN Age (yrs) Sex System Risk Activity Tx BRAFV600E (%) 1 56 F Multi High Inactive Yes 0 2 38 F Single High Inactive Yes 0 3 65 F Multi High Active Yes 2.59 4 48 M Single High Inactive Yes 0 5 41 F Single High Inactive Yes 0 6 28 M Multi High Inactive Yes 0 7 29 M Multi High Active No 1.00 8 47 F Multi High Active Yes 6.16 Discussion and Conclusion: PV and ET patients with WHO grade 1 marrow fibrosis manifest a phenotype that suggests progression to post-PV/ET myelofibrosis, and clinically overlap with PMF phenotype; however, these patients currently fail to meet 2008 IWG-MRT diagnostic criteria for this diagnosis on basis of sub-threshold fibrosis. MPN progression represents a biological spectrum and definitions of progression in ET/PV may benefit from other criteria not restricted by degree of fibrosis. Disclosures Mesa: Incyte, CTI, NS pharma, Gilead, Celgene: Research Funding.

Latium (Italy) Epidemiology of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms (MPNs) from 2011 to 2015: A Prospective Analysis from Gruppo Laziale of Ph Negative MPN

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5473-5473
Author(s):  
Marianna De Muro ◽  
Ambra Di Veroli ◽  
Marco Montanaro ◽  
Roberto Latagliata ◽  
Cristina Santoro ◽  
...  
Keyword(s):  
Incidence Rate ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Community Based ◽  
Thrombotic Risk ◽  
Inflammatory Bowel ◽  
Perspective Analysis ◽  
Observation Period

Abstract Background: MPNs including Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF), are clonal hematopoietic diseases in which the discovery of molecular driver mutations (JAK2, CALR, MPL) has deeply modified diagnostic approach in recent years. To date available data on epidemiology of MPNs and perspective analysis are rare. Our aim is to study the incidence of MPN Ph negative in a specific region of Italy named Latium and its variability across five years. Moreover we prospectively report the general features of our population. Method: We present here the prospective epidemiologic analysis of 1116 adult patients affected by MPNs (PV=289, ET=550, PMF=209) diagnosed according to 2008 WHO criteria, from January 2011 to December 2015 in 15 hematological Centers (5 academic and 10 community-based Hospitals) in Latium. A total of 289 PV, 550 ET and 209PMF were identified. The overall incidence rate of 289PV was 1.0/105 in 2011 and 2012, 1.1/105 in 2013, 0.9/105 in 2014 and 2015. The overall incidence rate of 550ET was 2.0/105 in 2011, 2.4/105 in 2012, 2.2/105 in 2013, 1.8/105 in 2014 and 1,2/105 in 2015 and the overall incidence rate of 209PMF was 0.7/105 in 2011 and 2012, 1.0/105 in 2013, 0.7/105 in 2014 and 0.5/105 in 2015. We have observed also 63 cases of MPNu (36M/32F) and the incidence rate was 0.3/105 in 2011 and 2012, 0.14/105 in 2013, 0.24/105 in 2014 and 0.22/105 in 2015. Baseline features of PV, ET and PMF patients are summarized in table 1. We have also analyzed the presence of comorbidities including obesity, arhythmia and neoplasia observed at the diagnosis in 1.6, 6.2 and 4% of all population, respectively; thirty-five percent of 1116 pts presented other comorbidities such as diabetes, inflammatory bowel disease, renal and liver failure. As thrombotic risk factors we considered diabetes, dislipidemia, smoke, essential hypertension and thrombophilia observed in 11,8, 16,2, 13,2, 51,7 and 3% of total pts, respectively. Conclusions: We confirm in our prospective observational protocol the overall incidence of MPN Ph negative, previously reported in the literature and the major incidence of male gender in PV and PMF, female in of ET. The annual incidence from 2011-2015 in Latium is remained substantially the same during the observation period. The decreasing trend observed in 2015 is probably due to the different update of some Centers that was done in October 2015 not including patients diagnosed in the last two months. Disclosures Latagliata: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Breccia:Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria. Cimino:Celgene: Honoraria; Bristol-Mayer: Honoraria.

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