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1
Hermouet, Sylvie, Eric Lippert, Niels Pallisgaard, Jiri Schwarz, Mary Frances McMullin, Lars Palmqvist, Heike L. Pahl, et al. "First Achievements of MPN&MPNr-EuroNet (COST Action BM0902), a New European Network Dedicated to the Diagnosis of Myeloproliferative Neoplasms and Hereditary Erythrocytosis and Thrombocytosis." Blood 118, no. 21 (November 18, 2011): 2809. http://dx.doi.org/10.1182/blood.v118.21.2809.2809.
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Abstract Abstract 2809 Background: The MPN&MPNr-EuroNet network, created in November 2009, is supported by the European program COST (CoOperation in Science and Technology). It is open to all colleagues active in the fields of myeloprolifeative neoplasms (MPN) and related hereditary diseases (MPNr: hereditary erythrocytosis and thrombocytosis). AIMS: To facilitate, improve and innovate in the diagnosis of MPN and hereditary erythrocytosis and thrombocytosis in Europe. Methods: MPN&MPNr-EuroNet has formed 4 working groups (WG): WG 1 focuses on JAK2 -mutated MPN; WG 2 is dedicated to thrombocythemia and myelofibroses without mutation of JAK2 and includes subgroups specialized in hereditary thrombocytosis (HT) and in histopathology; WG 3 is dedicated to hereditary erythrocytosis (HE); WG 4 is responsible for scientific cooperation and the diffusion of scientific knowledge. Results: During the first 18 months of MPN&MPNr-EuroNet activity, 77 colleagues from 19 countries (16 European countries plus Israel, Turkey, and the USA), joined the network and participated in the four WG, resulting in the achievements listed below. WG 1: 1) determination of the best JAK2 V617F assays, a joint MPN&MPNr-EuroNet/European LeukemiaNet project; 2) on-going study of MPN cases with low JAK2 V617F burden; 3) on-going study of MPN cases with multiple JAK2 mutation. WG 2: 1) list of laboratories responsible for the diagnosis of MPL and THPO mutations in Europe; 2) first international quality test of the detection of MPL mutations; 3) on-going study of new THPO and MPL mutations in HT cases; 4) on-going study of the histopathology of MPN without JAK2 mutation. WG 3: 1) list of laboratories responsible for the diagnosis of HE in Europe; 2) consensus on a diagnostic algorithm for the diagnosis of HE; 3) close interaction with COST Action TD0901 (HypoxiaNet) to facilitate the discovery of new genes of interest for the diagnosis of HE; 4) exchange of positive control samples for the main mutations responsible for HE; 5) study of idiopathic erythrocytosis. WG 4: 1) MPN&MPNr-EuroNet website: www.mpneuronet.eu; 2) organization of bi-annual meetings (5th meeting: March 7–9, 2012, Belfast, United Kingdom); 3) organization of annual training schools: a May training school dedicated to the molecular detection of JAK2 and MPL mutations (in Nîmes, France), and an October training school dedicated to hereditary erythrocytosis (in Coimbra, Portugal); 4) financial support for short term scientific missions for exchange and collaborative studies between participating institutions. Conclusion: MPN&MPNr-EuroNet will enable European researchers, biologists and clinicians to define new diagnostic tools and exchange technologies. MPN&MPNr-EuroNet is open to all interested physicians and scientists and we invite new members, including those from outside Europe, to join. Scholarships are available to finance participation in meetings and training schools, and to facilitate exchanges between participating institutions. For detailed information on all MPN&MPNr-EuroNet activities, see www.mpneuronet.eu. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Vannucchi:Novartis: Honoraria.
2
Mead, Adam J., and Ann Mullally. "Myeloproliferative neoplasm stem cells." Blood 129, no. 12 (March 23, 2017): 1607–16. http://dx.doi.org/10.1182/blood-2016-10-696005.
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Abstract Myeloproliferative neoplasms (MPNs) arise in the hematopoietic stem cell (HSC) compartment as a result of the acquisition of somatic mutations in a single HSC that provides a selective advantage to mutant HSC over normal HSC and promotes myeloid differentiation to engender a myeloproliferative phenotype. This population of somatically mutated HSC, which initiates and sustains MPNs, is termed MPN stem cells. In >95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in 1 of 3 genes: JAK2, CALR, or MPL. The thrombopoietin receptor, MPL, is the key cytokine receptor in MPN development, and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells. Despite common biological features, MPNs display diverse disease phenotypes as a result of both constitutional and acquired factors that influence MPN stem cells, and likely also as a result of heterogeneity in the HSC in which MPN-initiating mutations arise. As the MPN clone expands, it exerts cell-extrinsic effects on components of the bone marrow niche that can favor the survival and expansion of MPN stem cells over normal HSC, further sustaining and driving malignant hematopoiesis. Although developed as targeted therapies for MPNs, current JAK2 inhibitors do not preferentially target MPN stem cells, and as a result, rarely induce molecular remissions in MPN patients. As the understanding of the molecular mechanisms underlying the clonal dominance of MPN stem cells advances, this will help facilitate the development of therapies that preferentially target MPN stem cells over normal HSC.
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Hasselbalch, Hans Carl, Margitta Elvers, and Andrew I. Schafer. "The pathobiology of thrombosis, microvascular disease, and hemorrhage in the myeloproliferative neoplasms." Blood 137, no. 16 (April 22, 2021): 2152–60. http://dx.doi.org/10.1182/blood.2020008109.
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Abstract Thrombotic, vascular, and bleeding complications are the most common causes of morbidity and mortality in the Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs). In these disorders, circulating red cells, leukocytes, and platelets, as well as some vascular endothelial cells, each have abnormalities that are cell-intrinsic to the MPN driver mutations they harbor (eg, JAK2 V617F). When these cells are activated in the MPNs, their interactions with each other create a highly proadhesive and prothrombotic milieu in the circulation that predisposes patients with MPN to venous, arterial, and microvascular thrombosis and occlusive disease. Bleeding problems in the MPNs are caused by the MPN blood cell-initiated development of acquired von Willebrand disease. The inflammatory state created by MPN stem cells in their microenvironment extends systemically to amplify the clinical thrombotic tendency and, at the same time, preferentially promote further MPN stem cell clonal expansion, thereby generating a vicious cycle that favors a prothrombotic state in these diseases.
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Smalberg, Jasper H., Lidia R. Arends, Dominique C. Valla, Jean-Jacques Kiladjian, Harry L. A. Janssen, and Frank W. G. Leebeek. "Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis." Blood 120, no. 25 (December 13, 2012): 4921–28. http://dx.doi.org/10.1182/blood-2011-09-376517.
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Abstract Myeloproliferative neoplasms (MPNs) are the most common cause of Budd-Chiari syndrome (BCS) and nonmalignant, noncirrhotic portal vein thrombosis (PVT). In this meta-analysis, we determined the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders. MEDLINE and EMBASE databases were searched. Prevalence of MPNs, JAK2V617F, and MPN subtypes were calculated using a random-effects model. A total of 1062 BCS and 855 PVT patients were included. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% (95% CI, 32.9%-49.5%) and 41.1% (95% CI, 32.3%-50.6%), respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% (95% CI, 25.1%-38.8%) and 27.7% (95% CI, 20.8%-35.8%), respectively. JAK2V617F and MPNs were more frequent in BCS compared with PVT (P = .03 and P = .09, respectively). Polycythemia vera was more prevalent in BCS than in PVT (P = .001). JAK2V617F screening in splanchnic vein thrombosis (SVT) patients without typical hematologic MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively. These results demonstrate a high prevalence of MPNs and JAK2V617F in SVT patients and show differences in underlying etiology between these disorders. Furthermore, these results validate routine inclusion of JAK2V617F in the diagnostic workup of SVT patients.
5
Kim, Eunhee, and Omar Abdel-Wahab. "Focus on the epigenome in the myeloproliferative neoplasms." Hematology 2013, no. 1 (December 6, 2013): 538–44. http://dx.doi.org/10.1182/asheducation-2013.1.538.
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Abstract The discovery of mutations activating JAK-STAT signaling in the majority of patients with myeloproliferative neoplasms (MPNs) led to identification of tyrosine kinase activation as a predominant mechanism driving MPN pathogenesis. Despite this, the existence of additional genetic events that modify the MPN phenotype, predate JAK2 mutations, and/or contribute to leukemic transformation of MPNs has been suggested. Recently, mutations in several epigenetic modifiers have been described in patients with MPNs, including mutations in ASXL1, DNMT3A, EZH2, IDH1, IDH2, and TET2. Moreover, the mutant JAK2 itself has been shown recently to affect histone posttranslational modifications directly. Here we review the biological and clinical implications of epigenetic alterations in the pathogenesis of MPNs.
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Xu, Yue, Changxin Yin, Han He, Lingling Shu, Fuqun Wu, Fanyi Meng, Beng Chong, and Mo Yang. "Analysis of JAK2 V617F Mutation and Its Clinical Significance in Patients with Thrombocythemia and Other Myeloproliferative Neoplasms in Chinese." Blood 118, no. 21 (November 18, 2011): 4687. http://dx.doi.org/10.1182/blood.v118.21.4687.4687.
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Abstract Abstract 4687 JAK2 mutation is commonly found in Philadelphia-negative myeloproliferative neoplasms (MPNs). In Western countries, this mutation is found in approximately 96 percent of people with polycythemia vera, half of individuals with essential thrombocythemia or primary myelofibrosis. We used the method of amplification refractory mutation PCR (ARMS-PCR) to investigate MPN patients in China. We focused our study on patients with essential thrombocythemia (ET). ARMS-PCR was used to detect JAK2 V617F mutation in the bone barrow (BM) or peripheral blood of 37 MPN patients, which consisting of 7 ET, 5 polycythemia vera (PV), 5 chronic myeloid leukemia (CML), 5 chronic idiopathic myelofibrosis (CIMF), as well as 15 suspected MPNs. 17 cases of JAK2 V617F mutation (45.9%) were found in 37 patients, including 4 ET (57.1%), 4 PV (80.0%), 3 CIMF (60.0%), 6 suspected MPNs (40.0%). We did not find JAK2 V617F in the patients with CML. Our results indicated that the frequency of JAK2 V617F mutation in bcr/abl-negative MPNs in Chinese is similar to that in MPN patients in Western countries. At the same time, ARMS-PCR can distinguish the mutation is heterozygous or homozygous. Most patients were heterozygous for JAK2 but only a few were homozygous. In conclusion, our study showed that JAK2 V617F mutation frequency in Chinese MPN patients is similar to that in patients with this disorder in the West. It is the major molecular genetic abnormality in bcr-abl negative MPN and it can be used for diagnosis of MPN in China. Disclosures: No relevant conflicts of interest to declare.
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Zhang, Su-Jiang, Raajit Rampal, Taghi Manshouri, Jay Patel, Nana Mensah, Andrew Kayserian, Todd Hricik, et al. "Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome." Blood 119, no. 19 (May 10, 2012): 4480–85. http://dx.doi.org/10.1182/blood-2011-11-390252.
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Abstract Leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) is associated with a poor prognosis and resistance to therapy. Although previous candidate genetic studies have identified mutations in MPN patients who develop acute leukemia, the complement of genetic abnormalities in MPN patients who undergo LT is not known nor have specific molecular abnormalities been shown to have clinical relevance in this setting. We performed high-throughput resequencing of 22 genes in 53 patients with LT after MPN to characterize the frequency of known myeloid mutations in this entity. In addition to JAK2 and TET2 mutations, which occur commonly in LT after MPN, we identified recurrent mutations in the serine/arginine-rich splicing factor 2 (SRSF2) gene (18.9%) in acute myeloid leukemia (AML) transformed from MPNs. SRSF2 mutations are more common in AML derived from MPNs compared with LT after myelodysplasia (4.8%) or de novo AML (5.6%), respectively (P = .05). Importantly, SRSF2 mutations are associated with worsened overall survival in MPN patients who undergo LT in univariate (P = .03; HR, 2.77; 95% CI, 1.10-7.00) and multivariate analysis (P < .05; HR, 2.11; 95% CI, 1.01-4.42). These data suggest that SRSF2 mutations contribute to the pathogenesis of LT and may guide novel therapeutic approaches for MPN patients who undergo LT.
8
How, Joan, Amy Zhou, and Stephen T. Oh. "Splanchnic vein thrombosis in myeloproliferative neoplasms: pathophysiology and molecular mechanisms of disease." Therapeutic Advances in Hematology 8, no. 3 (December 8, 2016): 107–18. http://dx.doi.org/10.1177/2040620716680333.
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Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment. Other mutations commonly found in MPNs, including CALR and MPL, are rare in MPN-associated SVT. The purpose of this article is to review the clinical and molecular risk factors for MPN-associated SVT, with particular focus on the possible mechanisms of SVT formation in MPN patients.
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Ramanathan, Gajalakshmi, Brianna M. Hoover, and Angela G. Fleischman. "Impact of Host, Lifestyle and Environmental Factors in the Pathogenesis of MPN." Cancers 12, no. 8 (July 24, 2020): 2038. http://dx.doi.org/10.3390/cancers12082038.
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Philadelphia-negative myeloproliferative neoplasms (MPNs) occur when there is over-production of myeloid cells stemming from hematopoietic stem cells with constitutive activation of JAK/STAT signaling, with JAK2V617F being the most commonly occurring somatic driver mutation. Chronic inflammation is a hallmark feature of MPNs and it is now evident that inflammation is not only a symptom of MPN but can also provoke development and precipitate progression of disease. Herein we have considered major MPN driver mutation independent host, lifestyle, and environmental factors in the pathogenesis of MPN based upon epidemiological and experimental data. In addition to the traditional risk factors such as advanced age, there is evidence to indicate that inflammatory stimuli such as smoking can promote and drive MPN clone emergence and expansion. Diet induced inflammation could also play a role in MPN clonal expansion. Recognition of factors associated with MPN development support lifestyle modifications as an emerging therapeutic tool to restrain inflammation and diminish MPN progression.
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Masselli, Elena, Giulia Pozzi, Giuliana Gobbi, Stefania Merighi, Stefania Gessi, Marco Vitale, and Cecilia Carubbi. "Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants." Cells 9, no. 9 (September 21, 2020): 2136. http://dx.doi.org/10.3390/cells9092136.
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Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.
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Liisborg, Charlotte, Hans Carl Hasselbalch, and Torben Lykke Sørensen. "Ocular Manifestations in Patients with Philadelphia-Negative Myeloproliferative Neoplasms." Cancers 12, no. 3 (March 2, 2020): 573. http://dx.doi.org/10.3390/cancers12030573.
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The major complications of Philadelphia-negative (Ph-Negative) myeloproliferative neoplasms (MPNs) are thrombosis, haemorrhage and leukemic transformation. As systemic and haematological diseases, MPNs have the potential to affect many tissues and organs. Some complications lead to the diagnosis of MPNs, but other signs and symptoms are often misdiagnosed or neglected as a sign of MPN disease. Therefore, we reviewed the current literature to investigate and delineate the clinical manifestations seen in the eyes of Ph-negative MPN patients. We found that ocular manifestations are common among patients with MPNs. The most frequently described manifestations are due to the consequences of haematological abnormalities causing microvascular disturbances and hyperviscosity. More serious and vision-threatening complications as thrombotic events in the eyes have been repeatedly reported as well. These ocular symptoms may precede more serious extraocular complications. Accordingly, combined ophthalmological and haematological management have the potential to discover these diseases earlier and prevent morbidity and mortality in these patients. Furthermore, routine ophthalmological screening of all newly diagnosed MPN patients may be a preventive approach for early diagnosis and timely treatment of the ocular manifestations.
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Parthasarathy, Veda. "Myeloid Neoplasms in the Guise of Nutritional Deficiency." Case Reports in Hematology 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/826939.
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The classicBCR-ABL-negative myeloproliferative neoplasms (MPNs) which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are among the most frequent hematologic neoplasms. Because of their relatively smooth clinical course, it is likely that many of these MPNs actually go undetected. Considering the high prevalence of iron, folic-acid, and vitamin B12deficiencies in developing countries, their coexistence with MPN can be expected frequently. In such situations where both disorders coexist, MPN is often overlooked. This causes considerable diagnostic delay. In this paper, two cases of PMF and one case of PV where the diagnosis of MPN was delayed for about 3 years are discussed. Presence of concomitant vitamin B12, folate, and iron deficiencies perhaps camouflaged the underlying MPN. Bearing in mind the possibility of MPN, even in the setting of apparent nutritional deficiency and performing a bone marrow evaluation, is the crucial step in unveiling the hidden MPN.
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Kaufmann, Kai B., Albert Gründer, Tobias Hadlich, Julius Wehrle, Monika Gothwal, Ruzhica Bogeska, Thalia S. Seeger, et al. "A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2." Journal of Experimental Medicine 209, no. 1 (January 9, 2012): 35–50. http://dx.doi.org/10.1084/jem.20110540.
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The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase inhibitor (HDAC-I) vorinostat restored physiological levels of histone H3 acetylation, decreased NF-E2 expression, and normalized platelet numbers. Similarly, MPN patients treated with an HDAC-I exhibited a decrease in NF-E2 expression. These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies.
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Jutzi, Jonas S., Ruzhica Bogeska, Gorica Nikoloski, Corina A. Schmid, Thalia S. Seeger, Frank Stegelmann, Sven Schwemmers, et al. "MPN patients harbor recurrent truncating mutations in transcription factor NF-E2." Journal of Experimental Medicine 210, no. 5 (April 15, 2013): 1003–19. http://dx.doi.org/10.1084/jem.20120521.
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The molecular etiology of myeloproliferative neoplasms (MPNs) remains incompletely understood, despite recent advances incurred through the discovery of several different mutations in MPN patients. We have recently described overexpression of the transcription factor NF-E2 in MPN patients and shown that elevated NF-E2 levels in vivo cause an MPN phenotype and predispose to leukemic transformation in transgenic mice. We report the presence of acquired insertion and deletion mutations in the NF-E2 gene in MPN patients. These result in truncated NF-E2 proteins that enhance wild-type (WT) NF-E2 function and cause erythrocytosis and thrombocytosis in a murine model. NF-E2 mutant cells acquire a proliferative advantage, witnessed by clonal dominance over WT NF-E2 cells in MPN patients. Our data underscore the role of increased NF-E2 activity in the pathophysiology of MPNs.
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McMullin, Mary Frances, and Lesley Ann Anderson. "Aetiology of Myeloproliferative Neoplasms." Cancers 12, no. 7 (July 6, 2020): 1810. http://dx.doi.org/10.3390/cancers12071810.
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Myeloproliferative neoplasms (MPNs) have estimated annual incidence rates for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis of 0.84, 1.03, and 0.47 per 100,000. Prevalence is much higher, particularly for PV and ET, as mortality rates are relatively low. Patients are often concerned about why they developed an MPN and epidemiological studies enable the identification of potential causative factors. Previous work in small heterogeneous studies has identified a variety of risk factors associated with MPNs including family history of MPN, autoimmune conditions, some occupational exposures, and blood donation. At a population level, germline predisposition factors in various populations have been associated with MPNs. The pilot MOSAICC (Myeloproliferative Neoplasm: An In-depth Case-Control) study is one of the largest epidemiological studies in MPN ever carried out to date. It demonstrated the most effective methods for carrying out a significant epidemiological study in this patient group including the best way of recruiting controls, as well as how to evaluate occupational and lifestyle exposures, evaluate symptoms, and collect biological samples. Significant results linked to MPNs in the pilot study of 106 patients included smoking, obesity, and childhood socioeconomic status. The methodology is now in place for a much larger ongoing MOSAICC study which should provide further insight into the potential causes of MPNs.
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Lambert, Que T., Anuradha Pradhan, and Gary W. Reuther. "Pims: Potential Therapeutic Targets for Myeloproliferative Neoplasms." Blood 124, no. 21 (December 6, 2014): 4575. http://dx.doi.org/10.1182/blood.v124.21.4575.4575.
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Abstract Myeloproliferative neoplasms (MPNs) are a group of hematopoietic stem cell disorders characterized by the abnormal production of various myeloid cells. Aberrant JAK2 signaling (e.g. induced by JAK2-V617F) plays an etiological role in MPN formation. While JAK2 inhibitors improve patient symptoms, they do not induce cell death as neoplastic cells appear to be rather insensitive to JAK2 inhibition and effectively rapidly become resistant to treatment. Therefore, the development of additional therapeutic approaches for MPNs is needed. Pim kinases are serine/threonine kinases that protect hematopoietic cells from apoptosis and also play a role in regulating hematopoietic stem cell growth. In mouse models, elevated Pim expression contributes to the development of lymphoma. Pims are constitutively active and thus regulated by protein expression, which is controlled by Pim gene expression and Pim protein stability. Pim1 gene expression is normally induced by JAK2/STAT5 signaling in response to extracellular growth factor stimulation, as Pim1 is a direct transcriptional target of STAT5. The deregulated JAK2 signaling in MPNs also induces Pim expression. STAT5 is required for MPN disease in mouse models, suggesting genes transcriptionally regulated by STAT5 are required for MPN disease formation. Together with the anti-apoptotic signaling and transforming properties of Pims, this suggests Pims may play a role in MPNs. We hypothesized that Pim kinases may offer a therapeutic target for MPNs and that Pim kinase inhibitors in combination with JAK inhibitors may cause neoplastic cytotoxicity, improving on current JAK2-inhibitor mono-therapy for MPNs. JAK2-V617F-dependentMPN model cells (HEL, SET2, Uke1, and BaF3/JAK2-V617F, including cells that are resistant to the JAK2 inhibitor ruxolitinib) as well as MPN patient cells, were treated with Pim kinase inhibitors, SGI-1776 and AZD1208, and the JAK2 inhibitor, ruxolitinib. The effects on cell growth, cell cycle, viability, and cell signaling were studied. High concentration SGI-1776 (10 μM) inhibited cell growth and viability of MPN model cells while lower doses (1 and 3 μM) had little effect on the growth and viability of these cells. Combination of 3 μM SGI-1776 with low dose ruxolitinib significantly enhanced growth inhibition and cell death of HEL and SET2 cells. Similar results were obtained with the much more effective and selective Pim inhibitor, AZD1208. We show that ruxolitinib inhibits Pim expression in MPN cells, and Pim expression is restored in ruxolitinib-resistant cells. Importantly, low dose SGI-1776 or AZD1208 (100 nM) re-sensitized ruxolitinib-resistant MPN cells to ruxolitinib treatment. Significantly, as single agents, both SGI-1776 and AZD1208 inhibited erythropoietin-independent erythroid colony formation of primary cells from MPN patients, but not erythroid colonies of normal controls. The combination of AZD1208 and ruxolitinib exhibited enhanced inhibition of colony formation of primary cells from MPN patients compared to treatment with either drug alone. These data indicate that Pim kinase inhibitors in combination with a JAK2 inhibitor may offer a more efficacious therapeutic approach over JAK2 inhibitor mono-therapy for MPNs. Disclosures No relevant conflicts of interest to declare.
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Zhao, Wanke, Yanhong Du, Yun Chen, Wanting Ho, and Zhizhuang Joe Zhao. "The Role Of p53 In JAK2V617F-Induced Myeloproliferative Neoplasms." Blood 122, no. 21 (November 15, 2013): 4103. http://dx.doi.org/10.1182/blood.v122.21.4103.4103.
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Abstract Ph- myeloproliferative neoplasms (MPNs) are hematopoietic malignancies in which one or more myeloid lineages are abnormally amplified. These diseases represent a group of chronic conditions including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. MPNs mainly affect older people and have an average onset age of 55 years. Complications associated with MPNs include development of acute leukemia as well as thrombosis, hemorrhage, and myeloid metaplasia. JAK2V617F is found in the majority of patients with MPNs, and an overwhelming number of studies have demonstrated its pathogenicity. However, the precise action of JAK2V617F is not well defined, and other molecular defects involved in MPNs remain elusive. In earlier studies, we have generated transgenic mice expressing JAK2V617F in the hematopoietic system and demonstrated that JAK2V617F can cause MPN-like phenotypes in an age- and transgene dose-dependent manner. In this study, we address the involvement of tumor suppressor p53 in the progression of JAK2V617F-induced MPN phenotypes. We crossed our JAK2V617F transgenic mice with p53 knockout mice. Under the p53+/+ background, our JAK2V617F transgenic mice developed a mild MPN-like phenotypes in 15 weeks. However, under the heterozygous knockout p53-/+ condition, the mice developed a strong MPN-like phenotype in 8 weeks, manifested in higher blood cell counts, more severe splenomegaly, and earlier onset of myelofibrosis. This suggests that p53 affects the progression of MPNs, and reduced levels of p53 activity may be responsible for the heterogeneous phenotypes observed in MPN patients. Furthermore, when p53 was deleted from both chromosomes, JAK2V617F mice developed acute erythroleukemia, megakaryoblastic leukemia, or myeloid leukemia and died in 20 weeks with greatly enlarged spleen (>10 times the normal size) and liver (twice the normal size) infiltrated with leukemic cells. This indicates that loss of p53 in addition to JAK2V617F causes leukemic transformation. This is consistent with the earlier findings that p53 mutations exist in JAK2V617F-positive leukemia cell lines and JAK2V617F-positive MPNs patients who developed acute myeloid leukemia. Our study also suggests that targeting JAK2V617F and p53 simultaneously may provide effective treatment for MPNs. We employed nutlin-3 that disrupts the MDM2-p53 interaction thereby reducing degradation of p53. In vitro cell culture studies demonstrated that JAK2 inhibitors and nutlin-3 synergistically inhibited the growth of hematopoietic progenitor cells from JAK2V617F transgenic mice and MPN patients. Finally, from one of the p53-/- JAK2V617F transgenic mice, we derived an erythroleukemia cell line designated J53Z1. J53Z1 cells are CD71high and Ter119low and are dependent on erythropoietin for survival. They were effectively inhibited by known JAK2 inhibitors and should be useful in cell-based assays for screening of JAK2 inhibitors. Altogether, our study demonstrates that the level of p53 dictates the progression of JAK2V617F-induced MPNs and targeting p53 and JAK2V617F simultaneously may provide effective treatment for JAK2V617F-positive MNPs. Disclosures: No relevant conflicts of interest to declare.
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Pemmaraju, Naveen, Hagop M. Kantarjian, Jorge E. Cortes, Alfonso Quintas-Cardama, Sherry A. Pierce, and Srdan Verstovsek. "Incidence and Outcomes of Myeloproliferative Neoplasms (MPN) in Adolescents and Young Adults (AYAs)." Blood 120, no. 21 (November 16, 2012): 2845. http://dx.doi.org/10.1182/blood.v120.21.2845.2845.
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Abstract Abstract 2845 Background: The MPNs are a family of chronic hematologic malignancies that typically affect pts ages 60–70s. However, there is growing awareness of hematologic malignancies developing in young pts, particularly a unique subset of pts known as AYAs. Little is known about incidence and outcomes of AYA pts with MPNs. Objectives: To determine the incidence and outcomes of MPN AYA pts. Results: We retrospectively reviewed charts of 1,616 MPN pts evaluated at our institution from 1986–2011. A total of 171 MPN pts (11%) were identified whose ages were 16–39, defined as AYA pts (per NCCN guideline recommendations on AYA cancers). Breakdown by MPN subtype: Essential Thrombocytosis, ET (n=78, 46% of AYA MPNs), Polycythemia Vera, PV (n=25, 15%), Myelofibrosis, MF(n=24, 14%), [3 post-ET, 1 post-PV, 20 primary MF], Hypereosinophilic syndrome, HES (n=22, 13%), and Systemic Mastocytosis, SM (n=22, 13%). Baseline characteristics of AYA MPN pts detailed in Table 1. Only significant difference among AYA and non-AYA pts in terms of baseline CBC parameters was WBC: 6.4 (0.4–108.4) in AYA MF vs 10.1 (0.6–361) in non-AYA MF, p=0.0049. Analysis of median overall survival (OS), by Kaplan-Meier method, compared by age group (AYA vs non-AYA pts) and broken down by MPN subtype, shown in Table 2. Conclusion: MPN AYA pts constitute 11% of MPN pts at our institution. Overall, their 5- and 10- yr OS were significantly better than their older counterparts in the 3 major MPN subtypes (ET, PV, MF) and trended towards better survival but not statistically significant in HES and SM. Among AYA MPN pts, female predominance was noted among ET and SM pts and only 1 transformation event was noted among all MPN AYA pts in this analysis. Disclosures: No relevant conflicts of interest to declare.
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Yung, Yammy, Emily Lee, Hiu-Tung Chu, Pui-Kwan Yip, and Harinder Gill. "Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms." International Journal of Molecular Sciences 22, no. 2 (January 11, 2021): 659. http://dx.doi.org/10.3390/ijms22020659.
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Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.
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Yung, Yammy, Emily Lee, Hiu-Tung Chu, Pui-Kwan Yip, and Harinder Gill. "Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms." International Journal of Molecular Sciences 22, no. 2 (January 11, 2021): 659. http://dx.doi.org/10.3390/ijms22020659.
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Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.
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Kucine, Nicole, Amanda R. Leonti, Aishwarya Krishnan, Rhonda E. Ries, Ross L. Levine, and Soheil Meshinchi. "Transcriptome Profiling of Pediatric Myeloproliferative Neoplasms Demonstrates Dysregulation of Platelet-Relevant Genes and Enrichment of Inflammatory and JAK2 Mediated Complement Pathways." Blood 134, Supplement_1 (November 13, 2019): 4203. http://dx.doi.org/10.1182/blood-2019-125103.
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Introduction : Myeloproliferative neoplasms (MPNs) are rare clonal bone marrow disorders in children characterized by high blood counts, predisposition to clotting events, and the potential to transform to myelofibrosis or acute myeloid leukemia (AML). Children with MPNs have lower rates of the known driver mutations (in JAK2, MPL, and CALR) than adult patients, and the underlying pathways and molecular derangements in young patients remain unknown. Given the lack of knowledge about pediatric MPNs, it is critical that we gain a better understanding of the dysregulated pathways in these diseases, which is necessary for improving disease understanding and broadening treatment options in children. Therefore, the objective of this work was to identify differentially expressed genes and pathways between children with MPNs and healthy controls, as well as children with AML, to guide further study. Methods : Mononuclear cells were extracted from peripheral blood of pediatric MPN patients (n=20) and pediatric and young adult AML patients (n=1410), and bone marrow of normal controls (NC, n=68). AML patient samples were being evaluated as part of a Children's Oncology Group planned analysis. To identify an expression profile unique to MPNs, transcriptome data from MPN patients was contrasted against NC and AML patients. All samples were ribodepleted and underwent Illumina RNA-Seq to generate transcriptome expression data. All analyses were performed in R. Differentially expressed genes were identified using the voom function from the limma package (v. 3.38.3), and enriched pathways were identified using the pathfindR package (v. 1.3.1). Unsupervised hierarchical clustering and heatmap generation was performed using the ComplexHeatmap package (v. 1.20.0). Results : MPN patient samples showed a unique expression signature, distinct from both AML patients and normal controls. Unsupervised PCA plot (Figure 1A) and heatmaps (Figure 1B) show that MPN samples cluster together. There were 4,012 differentially expressed (DE) genes in MPNs compared to NC and 6,743 DE genes in MPNs compared to AML patients. There were 2,493 shared genes between the 2 groups (Figure 1C.) Significantly DE genes between MPNs and other groups included multiple platelet-relevant genes including PF4 (CXCL4), PF4V1, P2RY12, and PPBP (CXCL7). Interestingly, PF4V1 was the most DE gene in MPNs compared to AML, and third highest versus NC. Dysregulation of some of these genes has been seen in adult MPNs, as well as thrombosis. Further comparison of transcriptome profiles between children with (n=13) and without (n=7)JAK2 mutations showed upregulation of three genes, CFB, C2, and SERPING1, which are all known complement genes, implicating complement activation in JAK2-mutated MPN patients. Complement activation has previously been reported in adult MPNs. Pathway enrichment analysis shows a number of immune and inflammatory pathways as enriched in MPN patients compared to both AML and NC. There were 179 enriched pathways in MPNs compared to AML and 142 compared to NC, with 134 common pathways (Figure 1D.) The systemic lupus erythematosus pathway was the most heavily enriched pathway in MPNs compared to both AML and NC. Additional pathways with significant enrichment include hematopoietic cell lineage, cytokine-cytokine interactions, DNA replication, and various infection-relevant pathways. The JAK-STAT signaling pathway was also enriched in MPNs compared to both AML and NC, as was the platelet activation pathway. Conclusion: Transcriptome evaluation of childhood MPNs shows enrichment of numerous inflammatory and immune pathways, highlighting that, as in adult MPNs, inflammation is implicated in pediatric MPNs. Furthermore, specific complement genes were upregulated in JAK2-mutant MPN. Upregulation of platelet-specific genes implies potential insights into disease mechanisms and warrants more study. Variations in the cell populations may account for some of the differences seen, however all samples were largely mononuclear cells, making their comparisons reasonable. Further analysis of this early data is needed to better assess inflammatory changes and platelet activation in pediatric MPNs, as are larger sample sizes. Individual cells may have differential expression of various genes, and future experiments with single-cell RNA-seq would be helpful to further elucidate differences. Disclosures Levine: Novartis: Consultancy; Loxo: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Roche: Consultancy, Research Funding; Lilly: Honoraria; Amgen: Honoraria; Qiagen: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Isoplexis: Membership on an entity's Board of Directors or advisory committees.
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Wang, Min, Na He, Tian Tian, Lu Liu, Shuang Yu, and Daoxin Ma. "Mutation Analysis of JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in Chinese Patients with Myeloproliferative Neoplasms." BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/485645.
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Since the discovery of JAK2V617F tyrosine kinase-activating mutation, several genes have been found mutated in myeloproliferative neoplasms (MPNs). FLT3-ITD, NPM1, and DNMT3A mutations frequently occurred in AML patients and have been found conferred with myeloproliferative neoplasms in mouse model. Therefore, we sought to search for mutations in JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in 129 cases including 120 classic MPN cases and 9 MDS/MPN cases. JAK2V617F mutation was found in 60% of the 120 classic MPNs. However, none of the patients displayed FLT3-ITD and NPM1 mutations; only 2 patients harbored DNMT3A R882 mutation. Further studies including whole-genome sequence will be conducted to investigate the possible involvement of these genes in MPN.
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Abdel-Wahab, Omar, Taghi Manshouri, Jay Patel, Kelly Harris, Jin Juan Yao, Cyrus V. Hedvat, Adriana Heguy, et al. "TET2 and ASXL1 Mutations in Leukemic Transformation of Chronic Myeloproliferative Neoplasms." Blood 114, no. 22 (November 20, 2009): 2894. http://dx.doi.org/10.1182/blood.v114.22.2894.2894.
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Abstract Abstract 2894 Poster Board II-870 Recent studies have identified TET2 and ASXL1 mutations in myeloid malignancies, suggesting that acquisition of these mutant alleles might precede the acquisition of JAK2 in some myeloproliferative neoplasm (MPN) patients. Moreover, the observation that JAK2 mutations are observed in minority of patients with leukemic transformation of JAK2-mutant MPNs suggests the possibility that JAK2 mutations are dispensable for leukemic transformation. However the role of TET2 and ASXL1 mutations in leukemic transformation has not been evaluated. We therefore investigated the mutational status of JAK2, TET2, and ASXL1 in 63 patients with leukemic transformation from a pre-existing MPN, including 49 unpaired secondary acute myeloid leukemia (sAML) samples and 14 patients for whom paired MPN and sAML samples were available. Mutations of TET2 and ASXL1 were found at a higher frequency in sAML samples transformed from MPNs than reported for sporadic MPNs (9/46 (19.6%) and 7/46 (15.2%), respectively). This was also higher than the mutational frequency of TET2 and ASXL1 in de novo AML (6.4% (3/47) and 4.3% (2/47), respectively) but similar to that of AML transformed from MDS (12.8% (5/39) and 15.4% (6/39)). All possible genetic combinations of JAK2, TET2, and ASXL1 status were observed in sAML patients. Analysis of paired samples reveal that TET2 mutations are far more likely to occur at leukemic transformation of MPN than at MPN diagnosis (p=0.013, Fisher's exact test) whereas ASXL1 mutations were equally likely to occur at MPN or sAML. Although mutations in JAK2 and in TET2 may not be retained at leukemic transformation from MPN, mutations in ASXL1 at MPN diagnosis were consistently retained at leukemic transformation. In addition, individual cases were observed where TET2 and/or ASXL1 mutations were found before acquisition of JAK2 mutations or clinical evidence of MPN, as well as cases where TET2 and ASXL1 mutations were acquired during leukemic transformation of a JAK2V617F-positive clone. These data suggest the mutational order of events in MPN and sAML pathogenesis might vary in different patients, and that TET2 and ASXL1 mutations might contribute in different patients to the development of MPN and/or to leukemic transformation. In addition, the identification of transformed AML cases with no evidence of pre-existing JAK2, TET2, and ASXL1 mutations indicates the existence of other, not yet identified, mutations necessary for leukemic transformation of MPNs. Disclosures: Levine: Novartis: Research Funding; TargeGen: Consultancy. Verstovsek:Incyte: ; Exelixis: ; Cephalon: ; SBIO: ; AstraZeneca: .
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Martino, Bruno, Caterina Alati, Patrizia Cufari, Iolanda Vincelli, Francesca Ronco, Vincenzo Oriana, and Francesco Nobile. "Chronic Myeloprolipherative Neoplasms (MPNs) and Splanchnic Venous Thrombosis(SVT): Incidence and Risk Factors." Blood 116, no. 21 (November 19, 2010): 5057. http://dx.doi.org/10.1182/blood.v116.21.5057.5057.
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Abstract Abstract 5057 There is evidence in literature of the clinical and pathogenetic role of JAK2 V617F mutation in MPN, while its contribute as an additional thrombotic risk factor in MPN patients is still under discussion. The jak2 mutation has been identified as occult marker in several patients with splanchnic venous thrombosis (SVT); morover, 45% of patients with Budd-Chiari syndrome (BCS) and 34% of patients with portal vein thrombosis (PVT) have associated MPN. On the other hand, the majority of BCS patients without MPN present additional congenital or acquired thrombosis risk factors. The aim of the present study is to evaluate the incidence of SVT in MPN patients. We also evaluated the presence of other prothrombotic risk factors in MPN patients, in addition to the JAK-2 mutation. Out of the 460 Ph1 negative MPN patients observed in our center from January 2000 to January 2010 and retrospectively evaluated, 9 patients (7 females and 2 males; 2%) presented SVT. Six cases had Essential Thrombocythemia (ET), 2 Primary Myelofibrosis (PMF), and 1 Polycitemia Vera (PV). Five of the 6 cases with ET were females. Among the entire population of ET, SVT incidence was 3%. All the 9 patients diagnosed of SVT were JAK2 V617F positive and they were treated with antiaggregant and anticoagulation therapy; 6 received hydrossiurea. Seven patients had SVT before MPN diagnosis, 2 of them had splenectomy at diagnosis for surgical decision. In these patients developing SVT before MPN diagnosis no other major thrombotic event occurred during follow-up. The remaining 2 MPNs patients presented asymptomatic SVT diagnosed by imaging techniques routinely performed during MPN follow up. Interestingly, 75% of MPNs patients with SVT demonstrated at least one prothromobtic risk factor, such as factor V Leiden, Protein C deficiency, hyperhomocystinemia and 50% had 2 or more associated defects. MPNs patients without SVT (396) had a lower prevalence of prothrombotic risk factors and developed venous thrombosis in different anatomical sites: in these cases white blood cell count, platelets values and the presence of JAK2 V617F mutation correlate with the development of the thrombotic event. Conclusion. Even though SVT has a low incidence in MPNs patients, according to the results of the present retrospective study we suggest the potential benefit of searching for additional prothrombotic risk factors in the whole MPN population in order to prevent and/or properly treat this complication. Disclosures: No relevant conflicts of interest to declare.
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Yu, Jingbo, Dilan Paranagama, and Shreekant Parasuraman. "Recruitment strategies and geographic representativeness for patient survey studies in rare diseases: Experience from the living with myeloproliferative neoplasms patient survey." PLOS ONE 15, no. 12 (December 31, 2020): e0243562. http://dx.doi.org/10.1371/journal.pone.0243562.
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Background Recruitment of individuals with rare diseases for studies of real-world patient-reported outcomes is limited by small base populations. Myeloproliferative neoplasms (MPNs) are a group of rare, chronic, hematologic malignancies. In this study, recruitment strategies and geographic representativeness from the Living with MPNs survey are reported. Methods The Living with MPNs online cross-sectional survey was conducted between April and November 2016. Individuals 18 to 70 years of age living in the United States and diagnosed with an MPN were eligible to participate. Recruitment approaches included direct contact via emails and postcards; posts on MPN-focused social media and patient advocacy websites; postcard mailings to doctors’ offices; and advertisements on medical websites, Google, and Facebook. Geographic representativeness was assessed based on the number of survey respondents living in each state or the District of Columbia and by the number of survey respondents per 10 million residents. Results A total of 904 respondents with MPNs completed the survey. The recruitment method yielding the greatest number of respondents was advertisements on MPN-focused social media (47.6% of respondents), followed by emails (35.1%) and postcards (13.9%) sent through MPN advocacy groups. Home state information was provided by 775 respondents from 46 states (range of respondents per state, 1–89). The number of respondents per 10 million residents in the 46 states with respondents ranged from 12.1 to 52.7. Conclusions Recruitment using social media and communications through patient groups and advocacy organizations are effective in obtaining geographically representative samples of individuals with MPNs in the United States. These approaches may also be effective in other rare diseases.
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Andersen, Michael Asger, Ole Weis Bjerrum, Ajenthen Ranjan, Vibe Skov, Torben A. Kruse, Mads Thomassen, Axel Skytthe, Hans Carl Hasselbalch, and Kaare Christensen. "Myeloproliferative Neoplasms in Danish Twins." Acta Haematologica 139, no. 3 (2018): 195–98. http://dx.doi.org/10.1159/000488384.
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Objective: Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases characterized by clonal hyperproliferation of immature and mature cells of the myeloid lineage. Genetic differences have been proposed to play a role in the development of MPNs. Monozygotic twin pairs with MPNs have been reported in a few case reports, but the MPN concordance pattern in twins remains unknown. Method: All twin pairs born in the period 1900–2010 were identified in the nationwide Danish Twin Registry. Only pairs with both twins alive on January 1, 1977, and those born thereafter were included to allow identification in the Danish National Patient Registry. Results: A total of 158 twin pairs were registered with an MPN diagnosis: 36 monozygotic, 104 dizygotic, and 18 pairs with unknown zygosity. MPNs were diagnosed in both twins in 4 pairs. The probandwise concordance rates for monozygotic twin pairs were higher than for dizygotic twin pairs (15 vs. 0%; p = 0.016). Conclusion: An estimated concordance rate of 15% (95% CI 0.059–0.31) is modest, but given the rarity of MPNs this finding is clinically relevant and provides further support for the role of genetic predisposition in the development of MPNs.
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Naismith, Erin, Janine Steichen, Sieghart Sopper, and Dominik Wolf. "NK Cells in Myeloproliferative Neoplasms (MPN)." Cancers 13, no. 17 (August 31, 2021): 4400. http://dx.doi.org/10.3390/cancers13174400.
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Myeloproliferative neoplasms (MPNs) comprise a heterogenous group of hematologic neoplasms which are divided into Philadelphia positive (Ph+), and Philadelphia negative (Ph−) or classical MPNs. A variety of immunological factors including inflammatory, as well as immunomodulatory processes, closely interact with the disease phenotypes in MPNs. NK cells are important innate immune effectors and substantially contribute to tumor control. Changes to the absolute and proportionate numbers of NK cell, as well as phenotypical and functional alterations are seen in MPNs. In addition to the disease itself, a variety of therapeutic options in MPNs may modify NK cell characteristics. Reports of suppressive effects of MPN treatment strategies on NK cell activity have led to intensive investigations into the respective compounds, to elucidate the possible negative effects of MPN therapy on control of the leukemic clones. We hereby review the available literature on NK cells in Ph+ and Ph− MPNs and summarize today’s knowledge on disease-related alterations in this cell compartment with particular focus on known therapy-associated changes. Furthermore, we critically evaluate conflicting data with possible implications for future projects. We also aim to highlight the relevance of full NK cell functionality for disease control in MPNs and the importance of considering specific changes related to therapy in order to avoid suppressive effects on immune surveillance.
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Padron, Eric. "Surveying the landscape of MDS/MPN research: overlap among the overlap syndromes?" Hematology 2015, no. 1 (December 5, 2015): 349–54. http://dx.doi.org/10.1182/asheducation-2015.1.349.
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Abstract The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) lie at the interphase of phenotypically opposing bone marrow malignancies. They are characterized by concomitant features of bone marrow failure and myeloproliferation and are generally associated with a poor prognosis. Although much is unknown with respect to the clinical course and molecular biology of MDS/MPNs, emerging research is beginning to uncover the key defining characteristics of this designation. In this review, we will discuss the features of MDS/MPN diseases that unify there clinical and molecular course and those that define distinct disease entities. We will discuss advances in genetics and MDS/MPN modeling, as well as translational discoveries that are anticipated to inform the diagnosis, prognostication, and treatment of MDS/MPNs in the near future.
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Dhiman, Pratibha, and Priyanka Saxena. "JAK2V617F: Is It Sufficient as a Single Player in Splanchnic Venous Thrombosis?" Case Reports in Hematology 2015 (2015): 1–4. http://dx.doi.org/10.1155/2015/373490.
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Splanchnic venous thrombosis (SVT) includes thrombosis of the hepatic, portal, and mesenteric venous system. Myeloproliferative neoplasms (MPNs) are important factors of SVT in adults. Addition of JAK2V617F mutation in WHO criteria for diagnosis of MPNs has made this test a useful tool for diagnosis. JAK2 is an intracytoplasmic tyrosine kinase that plays a critical role in signal transduction from multiple hematopoietic factor receptors. The mutation is found frequently in patients with SVT; many such patients have no other manifestations of an MPN. Although the correlation of JAK2V617F mutation with thrombotic risk in MPNs has been shown in many studies, the impact of presence of additional thrombophilic factors in these cases is yet not known. As the management of MPNs remains highly dependent on the patient’s thrombotic risk, it is important to assess the thrombotic risk factors in detail. Here, we report two cases of JAK2V617F positive MPN who also had other thrombophilic conditions and presented with recurrent thrombosis.
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Vainchenker, William, Stefan N. Constantinescu, and Isabelle Plo. "Recent advances in understanding myelofibrosis and essential thrombocythemia." F1000Research 5 (April 19, 2016): 700. http://dx.doi.org/10.12688/f1000research.8081.1.
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The classicBCR-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. Thus, PMF is associated with both myeloproliferation and different levels of myelodysplastic features. MPNs are mostly driven by mutated genes called MPN drivers, which abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors. The recent discovery ofCALRmutations has closed a gap in our knowledge and has shown that this mutated endoplasmic reticulum chaperone activates the thrombopoietin receptor MPL and JAK2. These genetic studies have shown that there are two main types of MPNs: JAK2V617F-MPNs, including ET, PV, and PMF, and the MPL-/CALR-MPNs, which include only ET and PMF. These MPN driver mutations are associated with additional mutations in genes involved in epigenetics, splicing, and signaling, which can precede or follow the acquisition of MPN driver mutations. They are involved in clonal expansion or phenotypic changes or both, leading to myelofibrosis or leukemic transformation or both. Only a few patients with ET exhibit mutations in non-MPN drivers, whereas the great majority of patients with PMF harbor one or several mutations in these genes. However, the entire pathogenesis of ET and PMF may also depend on other factors, such as the patient’s constitutional genetics, the bone marrow microenvironment, the inflammatory response, and age. Recent advances allowed a better stratification of these diseases and new therapeutic approaches with the development of JAK2 inhibitors.
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Akada, Hajime, Saeko Akada, Dongqing Yan, Robert Hutchison, and Golam Mohi. "Loss of Wild-Type Jak2 Allele Enhances Myeloid Cell Expansion and Accelerates Myelofibrosis in Jak2V617F Knock-in Mice." Blood 120, no. 21 (November 16, 2012): 809. http://dx.doi.org/10.1182/blood.v120.21.809.809.
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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.
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How, Joan, and Gabriela Hobbs. "Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature." Cancers 12, no. 7 (July 18, 2020): 1954. http://dx.doi.org/10.3390/cancers12071954.
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Interferon alfa was first used in the treatment of myeloproliferative neoplasms (MPNs) over 30 years ago. However, its initial use was hampered by its side effect profile and lack of official regulatory approval for MPN treatment. Recently, there has been renewed interest in the use of interferon in MPNs, given its potential disease-modifying effects, with associated molecular and histopathological responses. The development of pegylated formulations and, more recently, ropeginterferon alfa-2b has resulted in improved tolerability and further expansion of interferon’s use. We review the evolving clinical use of interferon in essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). We discuss interferon’s place in MPN treatment in the context of the most recent clinical trial results evaluating interferon and its pegylated formulations, and its role in special populations such as young and pregnant MPN patients. Interferon has re-emerged as an important option in MPN patients, with future studies seeking to re-establish its place in the existing treatment algorithm for MPN, and potentially expanding its use for novel indications and combination therapies.
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Gamo, Masashi, and Tadashi Shoji. "A Method of Profiling Microbial Communities Based on a Most-Probable-Number Assay That Uses BIOLOG Plates and Multiple Sole Carbon Sources." Applied and Environmental Microbiology 65, no. 10 (October 1, 1999): 4419–24. http://dx.doi.org/10.1128/aem.65.10.4419-4424.1999.
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ABSTRACT A new approach to the community-level BIOLOG assay was proposed. This assay, which we call the BIOLOG-MPN assay, is a most-probable-number (MPN) assay that uses BIOLOG plates and multiple sole carbon sources, and the profiles obtained by this assay consist of MPNs estimated for the substrates in the BIOLOG plates. In order to demonstrate the performance of the BIOLOG-MPN assay, it was applied to pure cultures, model bacterial communities that contain two strains in different ratios, and microbial community samples. MPN estimation using BIOLOG plates worked well for the substrates on which utilizers can grow at a sufficiently high rate for color development under the conditions of the assay procedure. Furthermore, the results obtained using model communities showed that the MPNs obtained reflected the mixing ratios of pure cultures in the model communities. The profiles obtained using model communities and community samples were differentiated properly by statistical analyses. The results suggest that the BIOLOG-MPN assay is a promising procedure for obtaining a quantitative picture of the community structure.
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Yassin, Mohamed A., Hanadi Rafii El-Ayoubi, and Nader Al-Dewik. "Using Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) to Evaluate Quality of Life for MPN Patients in Qatar." Blood 120, no. 21 (November 16, 2012): 5069. http://dx.doi.org/10.1182/blood.v120.21.5069.5069.
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Abstract Abstract 5069 Background: Myeloproliferative neoplasms (MPNs), that is, essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a group of MPNs that can lead to significant rates of morbidity and mortality among affected patients. Specifically, patients in the early stages of these illnesses (ET, PV, and early MF) can be predisposed to thrombohemorrhagic events and vascular complications. Long-term complications of MPNs (either primary MF or MF arising from an antecedent ET or PV) can include progressive cytopenias, constitutional symptoms, cachexia and weight loss, moderate to massive splenomegaly, and risk of blastic transformation. Symptomatic burden in myeloproliferative neoplasms (MPNs) is present in most of MPN patients We sought to use broadly applicable instrument (MPN-SAF) to assess symptoms in myelofibrosis (MF), essential thrombocythemia (ET) and polycythemia vera (PV) among populations of Qatar. Methods: Using the MF-SAF as a base instrument, we added several key additional symptoms previously identified as present in all subtypes of MPNs including headaches, concentration, dizziness, extremity tingling, insomnia, sexual problems and mood changes on a 0 (absent) to 10 (worst-imaginable) scale. The MPN-SAF was administered jointly with the EORTC-QLQ-C30 as the co-validation instrument using prospective cohorts in Qatar (Patients referred to National Centre for Cancer Care and Research). Results: MPN-SAF Patient data: 123 MPN-SAF surveys were administered (English (45%), Arabic (55%) in 45 ET patients (36. 5 %%), 35 PV patients (28. 5%), and 15 MF patients (12. 2%), 28 MPN unclassified (22. 7%) an average of 7. 8 years (range 0 – 43 years) from their MPN diagnosis. Participants were of, age range (26 – 58 years) and gender (52% female) characteristic of disease. Prior hemorrhage (10%) and thrombosis (25%) were frequent. 78% of patients currently received cytoreductive therapy and 87% received cytoreductive therapy in the past. Patients and Symptomatic Burden: 19 items assessed in the MPN-SAF demonstrated consistently that the most common symptoms were decreased quality of life (93%), fatigue (84%), insomnia (65%), sad mood (65%), and sexuality problems (62%). The least common symptoms (<50% prevalence) were fevers (15%), weight loss (10%), abdominal pain (23%), cough (34%), headache (50%), and bone pain (48%). Symptoms were most severe in MF, followed by ET, then PV patients. Although symptoms are present in all 3 MPN subgroups, itching is notably more burdensome in PV patients (65%, median score of 2. 8 out of 10). Interestingly, night sweats (present in 58%). The majority found the MPN-SAF easy to understand (92%) and “addressed most of my MPN symptoms” (95%). Comparison to EORTC-QLQ-C30: Strong correlations existed between individual items represented on both the MPN-SAF and the EORTC-QLQC30 including pain, fatigue, appetite and insomnia (all p<0. 001). Additionally key symptomatic elements were highly correlated with the EORTC QLQ-C30 functional subscales. Comparison to Physician Perceptions: Comparison of the results of the MPN-SAF to enrolling physicians' blinded opinion of patients symptoms (8 assessed - night sweats, fevers, fatigue, weight loss, bone pain, and pruritus) showed excellent correlation with corresponding patients' responses (all p<0. 001). Serial MPN-SAF Results: Pearson correlations indicate that most MPN-SAF items are well correlated (r >0. 5, p<. 001) upon repeat survey administration. Items characteristic of advanced disease, including weight loss, fever, and cough displayed lower Pearson correlations (r=0. 46, −0. 08, and 0. 38 respectively). Conclusions: The MPN-SAF is comprehensive and reliable instrument which is available in multiple languages (including Arabic and English) to evaluate MPN-associated symptoms. The MPN-SAF is recommended as a uniform symptom assessment tool for MPN patient. Disclosures: Yassin: Qatar National Research Fund: Patents & Royalties, Research Funding. Off Label Use: use of pegelated interferon alfa 2a in treatment of patients with ET. Rafii El-Ayoubi:Qatar National Research Fund: Patents & Royalties, Research Funding. Al-Dewik:Qatar National Research Fund: Patents & Royalties, Research Funding.
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Woods, Gary M., Rajinder P. S. Bajwa, Samir B. Kahwash, and Terri Guinipero. "Secondary Acute Myeloid Leukemia in a One-Year-Old Girl Diagnosed with JAK2-V617F Mutation Positive Myeloproliferative Neoplasm." Case Reports in Medicine 2014 (2014): 1–4. http://dx.doi.org/10.1155/2014/473297.
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Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by hyperproliferation of hematologic cell lines and have been associated with tyrosine kinase JAK2-V617F mutations. Secondary acute myeloid leukemia (sAML) is a known complication of JAK2-V617F+ MPNs and bears a poor prognosis. Although the evolution of a JAK2-V617F+ MPN to a mixed-lineage leukemia has been reported in the pediatric population, no evolutions into sAML have been described. We present a case of a one-year-old girl diagnosed with JAK2-V617F+ MPN with evolution into sAML. Despite initial morphologic remission, she eventually relapsed and succumbed to her disease.
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Koschmieder, Steffen. "How I Manage Thrombotic/Thromboembolic Complications in Myeloproliferative Neoplasms." Hämostaseologie 40, no. 01 (February 2020): 047–53. http://dx.doi.org/10.1055/s-0040-1701474.
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AbstractPatients with myeloproliferative neoplasms (MPNs), such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are at increased risk for arterial and venous thrombosis/thromboembolism. In particular, the risk of splanchnic venous thrombosis, such as portal vein thrombosis or Budd–Chiari syndrome, is significantly higher in patients with MPN than in the normal population. At the same time, MPN patients are at increased risk for severe bleeding. Therefore, the treatment of patients with MPN must be based on their suspected probability of thrombosis/thromboembolism and bleeding. For this purpose, patient and MPN-specific risk factors are used. Patients at expected high risk of thrombosis should receive adequate primary or secondary thromboprophylaxis in addition to cytoreductive therapy. This may consist of antiplatelet agents and/or anticoagulant agents and must be balanced with the individual bleeding risk. The goal is to increase the quality of life and life span of patients with MPNs by preventing (re-)thrombosis and severe bleeding.
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Hermouet, Sylvie, Edith Bigot-Corbel, and Betty Gardie. "Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation." Mediators of Inflammation 2015 (2015): 1–16. http://dx.doi.org/10.1155/2015/145293.
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Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal diseases characterized by the excessive and chronic production of mature cells from one or several of the myeloid lineages. Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in theJAK2, MPL,orCALRgenes. Yet the roles played by these mutations in the pathogenesis and main complications of the different subtypes of MPNs are not fully elucidated. Importantly, chronic inflammation has long been associated with MPN disease and some of the symptoms and complications can be linked to inflammation. Moreover, the JAK inhibitor clinical trials showed that the reduction of symptoms linked to inflammation was beneficial to patients even in the absence of significant decrease in theJAK2-V617F mutant load. These observations suggested that part of the inflammation observed in patients withJAK2-mutated MPNs may not be the consequence ofJAK2mutation. The aim of this paper is to review the different aspects of inflammation in MPNs, the molecular mechanisms involved, the role of specific genetic defects, and the evidence that increased production of certain cytokines depends or not on MPN-associated mutations, and to discuss possible nongenetic causes of inflammation.
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Hansasuta, Ake, R. Shane Tubbs, and Paul A. Grabb. "Surgical Relationship of the Medial Pectoral Nerve to the Musculocutaneous Nerve: A Cadaveric Study." Neurosurgery 48, no. 1 (January 1, 2001): 203–7. http://dx.doi.org/10.1097/00006123-200101000-00037.
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Abstract OBJECTIVE For purposes of neurotization of the musculocutaneous nerve (MCN) with the medial pectoral nerve (MPN) after upper trunk brachial plexus injuries, the anatomic relationship between these two nerves was defined in a cadaveric model. METHODS Thirty-five brachial plexuses in 18 adult cadavers were dissected. The distance between the origin of the MPN from the medial cord to the origin of the MCN from the lateral cord was measured. The length, diameter, branching, and location of the MPN were recorded. The diameter of the proximal MCN was recorded. RESULTS Thirty-seven percent of the MPNs, when detached from the pectoralis muscles, were too short to reach the proximal MCN by a mean distance of 15 mm. The MPN pierced the pectoralis minor muscle in 80% of the dissections. The cross sectional area of the MCN was always larger than the cross sectional area of the MPN by an average factor of 2.5. CONCLUSION When planning to use the MPN for neurotization of the MCN, one should be prepared to harvest an interposition graft, because over one-third of MPNs may not have enough length to reach the MCN in a tension-free manner. Diameter mismatch occurs predictably between the distal MPN and the proximal MCN.
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Hultcrantz, Malin, Therese M.-L. Andersson, Ola Landgren, Paul W. Dickman, Bjorn Andreasson, Magnus Bjorkholm, and Sigurdur Y. Kristinsson. "A Population-Based Study of Incidence of Myeloproliferative Neoplasms in Sweden Between 2000 and 2012." Blood 126, no. 23 (December 3, 2015): 1605. http://dx.doi.org/10.1182/blood.v126.23.1605.1605.
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Abstract Background The Myeloproliferative neoplasms (MPNs) consists of the subtypes polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and MPN unclassifiable (MPN-U). The incidence rates of these diseases vary substantially between different reports, ranging from 1.15 to 4.99/100,000 person-years. However, in a recent metaanalysis, there was no significant difference in MPN incidence between Europe and North America and the variations in incidence may therefore reflect the quality of the cancer registers and reporting of MPNs. In addition, there is a limited number of reports on MPN incidence during more recent years. Therefore, we assessed the incidence of MPN based on the Swedish Cancer Register, a high-quality population-based cancer register between 2000 and 2012. Patients and Methods The Swedish Cancer Register was used to identify all patients diagnosed with an MPN between January 1st 2000 and December 31st 2012. These Swedish Cancer Registers have very high levels of quality and completeness. Between 2008 and 2012, the reporting of newly diagnosed MPN to the cancer register was >92%. Information on the Swedish population was obtained from the Human Mortality Database (www.mortality.org). Based on information from these registers, incidence rates of MPNs with 95% confidence intervals (CIs) were calculated. Confidence intervals were estimated on the log scale. In addition, the incidence rate in relation to MPN subtype, age group (18-39, 40-49, 50-59, 60-69, 70-79, and ³80 years), as well as calendar year of diagnosis was assessed. Results A total of 5,442 MPN patients were reported to the cancer register between 2000 and 2012. During these years, there were 1,810 incident cases of PV, 1,862 of ET, 636 of PMF, and 1,134 with MPN-U. Between January 1st 2000 and December 31st 2012, the population in Sweden increased from 8,861,426 to 9,555,893 inhabitants. The overall annual incidence rate of MPN was 5.83 (95% CI 5.68-5.99)/100,000 persons. The incidence rate of PV was 1.94 (1.85-2.03), ET 2.00 (1.91-2.09), PMF 0.68 (0.63-0.74), and MPN-U 1.22 (1.15-1.29) per 100,000 person-years. In addition, there was a strong correlation between age and incidence of MPN with incidence rates being substantially higher among the older age groups (Table). The overall incidence rate of MPNs increased during the study period, from 5.06 (4.55-5.62)/100,000 person-years in the year 2000 to 5.98 (5.45-6.55)/100,000 person-years in 2012. The incidence rate of PV was similar throughout the study period, the incidence was 2.05 (1.74-2.42)/100,000 person-years in 2000 and 2.12 (1.81-2.47)/100,000 person-years in 2012. The annual incidence rate of ET and PMF increased, from 1.62 (1.34-1.95) to 2.49 (2.15-2.87) per 100,000 persons for ET and from 0.36 (0.24-0.53) to 0.86 (0.67-1.10) per 100,000 persons for PMF between 2000 and 2012. Conversely, the incidence of MPN-U decreased, 1.03 (0.81-1.29) to 0.52 (0.38-0.71)/100,000 person-years between 2000 and 2012. Summary and Conclusions In this large population-based study, the incidence of MPN was higher than previously reported in both European and North American studies. As earlier lower incidence rates likely are an effect of limited coverage of cancer registers, there may be an underreporting of MPNs in many European and American countries. The increase in MPN incidence rates during the study period may reflect increasing life expectancy of the Swedish population, improved reporting to the cancer register as well as changes in the classification and diagnostic systems. Similarly, the decrease in incidence of MPN-U is also likely a result of improved diagnostics during more recent years. In conclusion, the MPN incidences rates reported here are presumably more accurate compared to earlier reports due to the high level of coverage and accuracy of the Swedish registers. Table 1. Incidence rates of MPNs overall and in relation to subtype and age at diagnosis Total number MPN diagnosed 2000-2012 Incidence/100 000 person-years (95% confidence interval) All MPN 5,442 5.83 (5.68-5.99) Subtype PV 1,810 1.94 (1.85-2.03) ET 1,862 2.00 (1.91-2.09) PMF 636 0.68 (0.63-0.74) MPN-U 1,134 1.22 (1.15-1.29) Age at diagnosis (years) 18-39 226 0.67 (0.59-0.76) 40-49 361 2.26 (2.04-2.51) 50-59 769 4.92 (4.58-5.28) 60-69 1,228 9.54 (9.02-10.1) 70-79 1,680 18.99 (18.1-19.9) >80 1,178 18.92 (17.87-20.03) Disclosures Landgren: BMJ Publishing: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; Onyx: Honoraria; Celgene: Honoraria; International Myeloma Foundation: Research Funding; Medscape: Consultancy; BMJ Publishing: Consultancy; Onyx: Research Funding; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Celgene: Consultancy.
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Palomo, Laura, Manja Meggendorfer, Stephan Hutter, Sven Twardziok, Vera Ademà, Irene Fuhrmann, Francisco Fuster-Tormo, et al. "Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms." Blood 136, no. 16 (October 15, 2020): 1851–62. http://dx.doi.org/10.1182/blood.2019004229.
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Abstract More than 90% of patients with myelodysplastic/myeloproliferative neoplasms (MDSs/MPNs) harbor somatic mutations in myeloid-related genes, but still, current diagnostic criteria do not include molecular data. We performed genome-wide sequencing techniques to characterize the mutational landscape of a large and clinically well-characterized cohort including 367 adults with MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 119), atypical chronic myeloid leukemia (aCML; n = 71), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 71), and MDS/MPN unclassifiable (MDS/MPN-U; n = 106). A total of 30 genes were recurrently mutated in ≥3% of the cohort. Distribution of recurrently mutated genes and clonal architecture differed among MDS/MPN subtypes. Statistical analysis revealed significant correlations between recurrently mutated genes, as well as genotype-phenotype associations. We identified specific gene combinations that were associated with distinct MDS/MPN subtypes and that were mutually exclusive with most of the other MDSs/MPNs (eg, TET2-SRSF2 in CMML, ASXL1-SETBP1 in aCML, and SF3B1-JAK2 in MDS/MPN-RS-T). Patients with MDS/MPN-U were the most heterogeneous and displayed different molecular profiles that mimicked the ones observed in other MDS/MPN subtypes and that had an impact on the outcome of the patients. Specific gene mutations also had an impact on the outcome of the different MDS/MPN subtypes, which may be relevant for clinical decision-making. Overall, the results of this study help to elucidate the heterogeneity found in these neoplasms, which can be of use in the clinical setting of MDS/MPN.
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Gowin, Krisstina, Caroline Irene Piatek, Siamak Saadat, Karren Cuadra, Pedram Razavi, Ronald Tang, and Casey L. O'Connell. "Patients with Polycythemia Vera and Essential Thrombocytosis Have a Higher Risk of Prior or Concurrent Tumors Compared to Patients with Secondary Thrombocytosis." Blood 116, no. 21 (November 19, 2010): 3084. http://dx.doi.org/10.1182/blood.v116.21.3084.3084.
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Abstract Abstract 3084 Background Polycythemia vera (PV) and Essential thrombocytosis (ET) are chronic myeloproliferative neoplasms (MPNs) that arise from aberrant, clonal hematopoietic stem cells. MPNs are associated with an elevated risk of arterial and venous thrombosis as well as with transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). Diseases causing secondary, or reactive, elevation of the red cell or platelet counts are not considered clonal and do not predispose to the development of hematologic malignancies. Prior reports in patients of European descent suggest as many as 15% of patients with MPNs die of unrelated malignancies, but there is no data suggesting that these malignancies precede the MPN diagnosis. In a large, ethnically diverse population, we investigated whether tumors other than MF or AML (“unrelated tumors”) occurred more commonly among patients with ET and PV than among patients with secondary thrombocytosis. Methods We performed a retrospective chart review of all consecutive patients diagnosed with ET, PV or secondary thrombocytosis (ST) between April, 1992 and June, 2010. Laboratory data and the World Health Organization criteria were utilized to distinguish ET, PV and ST. In addition to demographic and MPN-specific diagnostic data and complication rates, we recorded the prior or concurrent, pathologically-confirmed diagnosis of unrelated tumors, their histology and treatment received. We performed a multivariate, exact logistic regression analysis adjusted for age at diagnosis of MPN, sex, ethnicity, JAK2 mutational status and MPN subtype to determine whether MPN patients are more likely to have had unrelated tumors than ST patients. Results Seventy-six patients with MPNs, 55 with ET and 21 with PV, were compared to 82 patients with ST. The median age at diagnosis in the MPN group was 53.5 years (range 19 –84); it was 46 years in the ST group (range 16 – 87). The majority (57.9%) of the patients with MPNs were Hispanic whites, 21% were Asian, 15.8% were non-Hispanic whites, and 5.3% were Black. Of the 82 patients with ST, 73.2% were Hispanic whites, 9.8% were Asian, 9.8% were Black and 4.9% were non-Hispanic whites. Thrombosis occurred in 12 (15.8%) of the MPN patients and in none of the ST patients. We observed a statistically significantly higher incidence of unrelated tumors in MPN patients (17.1%) as compared to ST patients (1.2%). The multivariate analysis revealed an odds ratio for unrelated tumors among MPN patients of 5.19 (95% CI 1.04 – 22.1, p = 0.038) compared to ST patients. Of the 13 unrelated tumors which were diagnosed among patients with MPN, 11 were diagnosed prior to the MPN diagnosis and included 5 breast cancers (2 treated surgically, 2 treated with surgery, radiation and chemotherapy, 1 treated with surgery and radiation only); 3 neural tumors including 1 meningioma, 1 pituitary macroadenoma, and 1 schwannoma (all treated with surgery alone); 2 hematologic malignancies including a low grade B-cell lymphoma and a rectal MALT lymphoma (1 treated with combination chemotherapy and 1 treated with Rituxan alone); and 1 prostate cancer (treated with hormonal therapy alone). Two patients developed unrelated tumors during the course of their MPN; these included 1 patient with gastrointestinal stromal tumor and 1 with multiple myeloma. Interestingly, the latter patient has maintained a normal platelet count without cytoreductive ET therapy for the 18 months since autologous transplant for his myeloma. Conclusions Patients with PV and ET have a significantly higher risk of having prior or concurrent tumors unrelated to progression of their MPN when compared to patients with ST. Disclosures: No relevant conflicts of interest to declare.
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ROTH, LAWRENCE A., HAROLD BENGSCH, CHARLES DAVIDSON, and JAMES S. DICKSON. "Extended Incubation of LST and BGB Tubes and the MPN Estimates of Coliforms." Journal of Food Protection 57, no. 8 (August 1, 1994): 740–42. http://dx.doi.org/10.4315/0362-028x-57.8.740.
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Extending the incubation time past the standard 48 h for presumptive lauryl sulfate tryptose (LST) broth and confirmed brilliant green bile (BGB) broth tests for coliforms resulted in increases in most probable number (MPN) estimates. Whereas 40% of the samples showed an increase in the presumptive MPN when the incubation was extended from 48 to 72 h, only 5% showed confirmed MPNs, which exceeded the 95% confidence limits established for the 48-h confirmed MPNs. Extending the incubation of BGB tubes to 72 h resulted in less than 5% of the samples exhibiting increased MPNs, which exceeded the 48-h 95% confidence limits. Some loss in viability of coliforms was observed when LST tubes were incubated beyond 72 h. The study demonstrates the importance of adhering to standard incubation times for interlaboratory comparisons and ensuring regulatory compliance.
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Davis, Keith L., Gregory L. Price, Sudeep Karve, Gerhardt M. Pohl, and Richard A. Walgren. "Comorbidity Burden in Elderly Persons with Non-CML Myeloproliferative Neoplasms: Real-World Evidence From a United States Medicare Population." Blood 120, no. 21 (November 16, 2012): 1734. http://dx.doi.org/10.1182/blood.v120.21.1734.1734.
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Abstract Abstract 1734 Background: Non-CML myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF) and MPN not otherwise specified (MPN-NOS), are characterized by activation of JAK2 signaling and abnormal blood cell production. MPN patients, especially those aged ≥65 years (in whom MPN incidence is highest), are at increased risk for cardiovascular and other comorbidities (Vannucchi et al. Blood 2007;110:840-6, Marchioli et al. J Clin Oncol 2005;23:2224-32). However, comorbidity rates in elderly MPN patients as compared with non-MPN controls have not been described in previous literature. MPNs are more prevalent in the elderly and therefore Medicare enrollees are a highly relevant source for US-based epidemiological data for these diseases. Objective: To compare comorbidity rates from four subtypes of elderly MPN patients (ET, PV, MF and MPN-NOS) with matched non-MPN/non-cancer controls. Methods: Retrospective data were taken from the Survey, Epidemiology, and End Results (SEER)-Medicare linked database in the US, which combines clinical information from the SEER cancer registry (MPN reporting has been required since 2001) with medical and pharmacy claims for Medicare enrollees. Patients with a new MPN diagnosis between Jan 1, 2001 and Dec 31, 2007 were selected and evaluated for comorbidities from Jan 1, 2008 (index date) through Dec 31, 2008 (follow-up end date). Patients were classified by MPN subtype based on the most recent diagnosis information (ICD-O-3 from the SEER registry or ICD-9-CM from Medicare claims) before the index date. Patients who died before follow-up end, had HMO or discontinuous Medicare enrollment during the follow-up year, had enrollment based on end stage renal disease, or were diagnosed with a non-MPN malignancy before follow-up end were excluded. Comorbidities were defined by ICD-9-CM diagnosis codes comprising the Charlson Comorbidity Index (CCI) (Charlson et al. J Chron Dis 1987;40:373–83; Deyo et al. J Clin Epidemiol 1992;45:613-9) as well as other adverse conditions. Separate non-MPN/non-cancer control groups were selected for each MPN subtype and matched (5:1) on birth year, gender, ethnicity, geography, and reason for Medicare eligibility. The proportion of patients with individual comorbidities and mean CCI during the follow-up year were compared between MPN cases and controls using univariate chi-square tests and t-tests. Results: A total of 1,355 MPN patients (n = 445 ET, 684 PV, 81 MF, 145 MPN-NOS) were identified for inclusion and assigned matching controls. For ET, PV, MF and MPN-NOS cases, respectively, mean [SD] age at index was 75.5 [9.7], 70.8 [11.3], 70.8 [10.4] and 74.1 [8.9] years and % female was 69.0, 43.9, 54.3, and 55.2. Mean [SD] years between first MPN diagnosis and study index date was 3.1 [2.0], 3.4[1.9], 2.7 [2.0], and 3.1 [2.1] for ET, PV, MF and MPN-NOS cases, respectively. Comorbidity rates during the follow-up period for MPN cases and matched controls are shown in the figure. Compared with controls, ET, PV and MPN-NOS cases had significantly (p<0.05) higher rates of serious cardiovascular events and comorbidities during the follow-up year, including myocardial infarction (ET vs. control: 8.1% vs. 4.0%, PV vs. control: 8.6% vs. 4.3%, MPN-NOS vs. control: 9.7% vs. 5.0%), congestive heart failure (CHF) (ET vs. control: 16.4% vs. 12.7%, PV vs. control: 18.4% vs. 10.1%, MPN-NOS vs. control: 22.1% vs. 12.4%), peripheral vascular disease (PVD) (ET vs. control: 20.0% vs. 15.4%, PV vs. control: 19.4% vs. 13.6%, MPN-NOS vs. control: 27.6% vs. 15.7%), and stroke (ET vs. control: 17.8% vs. 13.4%, PV vs. control: 17.8% vs. 13.1%, MPN-NOS vs. control: 22.1% vs. 13.9%). MF cases also had higher rates of CHF, PVD and stroke, but due to small sample size, only congestive heart failure was significant. Other comorbidities were significantly higher in all MPN subtypes, notably thromboembolism, renal disease, moderate-to-severe liver disease, and infections. Conclusions: Medicare enrollees with MPNs generally experienced significantly higher comorbidity rates and overall comorbidity burden (based on mean CCI scores) than matched controls. These findings have implications for both the clinical management of MPN patients as well as for health economic assessments, since a substantial portion of the cost of care for MPNs may reside in treatment of comorbidities not directly coded to MPNs. Disclosures: Davis: Eli Lilly, Merck, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, Eisai, Sanof-Aventis, Gilead Sciences, MedImmune: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Price:Eli Lilly and Company: Employment, Equity Ownership. Karve:RTI Health Solutions: Consultancy, Research Funding. Pohl:Eli Lilly and Company: Employment, Equity Ownership. Walgren:Eli Lilly and Company: Employment, Equity Ownership.
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Karantanos, Theodoros, Shruti Chaturvedi, Evan M. Braunstein, Jerry Spivak, Linda Resar, Styliani Karanika, Donna M. Williams, Ophelia Rogers, Christopher D. Gocke, and Alison R. Moliterno. "Sex determines the presentation and outcomes in MPN and is related to sex-specific differences in the mutational burden." Blood Advances 4, no. 12 (June 15, 2020): 2567–76. http://dx.doi.org/10.1182/bloodadvances.2019001407.
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Abstract The factors underlying the variable presentation and clinical course of myeloproliferative neoplasms (MPNs) remain unclear. The aim of this study was to evaluate the independent effect of sex on MPN presentation and outcomes. A total of 815 patients with essential thrombocytosis, polycythemia vera, or primary myelofibrosis were evaluated between 2005 and 2019, and the association of sex with presenting phenotype, JAK2 V617F burden, progression, and survival was examined. Men presented more often with primary myelofibrosis vs essential thrombocytosis (relative risk, 3.2; P < .001) and polycythemia vera (relative risk, 2.1; P < .001), had higher rates of transformation to secondary myelofibrosis (hazard ratio [HR], 1.55; P = .013) and acute myeloid leukemia (HR, 3.67; P < .001), and worse survival (HR, 1.63; P = .001) independent of age, phenotype at diagnosis, and MPN-specific mutation. Men had higher JAK2 V617F allele burdens in their CD34+ cells (P = .001), acquired more somatic mutations (P = .012) apart from the MPN-specific mutations, and had an increased frequency of 1 (odds ratio, 2.35; P = .017) and 2 (odds ratio, 20.20; P = .011) high-risk mutations independent of age, phenotype, and driver mutation. Male sex is an independent predictor of poor outcomes in MPNs. This seems to be due to an increased risk of non–MPN-specific somatic mutations, particularly high-risk mutations, rather than MPN-specific mutation allele frequency. Conversely, disease progression in female subjects is more dependent on JAK2 mutation allele burden than on acquisition of other somatic mutations. Sex should be considered in prognostic models and when evaluating therapeutic strategies in MPNs.
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Allain-Maillet, Sophie, Adrien Bosseboeuf, Nicolas Mennesson, Mégane Bostoën, Laura Dufeu, Eun Ho Choi, Cédric Cleyrat, et al. "Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms." Cancers 12, no. 9 (August 28, 2020): 2446. http://dx.doi.org/10.3390/cancers12092446.
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Inflammatory cytokines play a major role in myeloproliferative neoplasms (MPNs) as regulators of the MPN clone and as mediators of clinical symptoms and complications. Firstly, we investigated the effect of JAK2V617F on 42 molecules linked to inflammation. For JAK2V617F-mutated patients, the JAK2V617F allele burden (%JAK2V617F) correlated with the levels of IL-1β, IL-1Rα, IP-10 and leptin in polycythemia vera (PV), and with IL-33 in ET; for all other molecules, no correlation was found. Cytokine production was also studied in the human megakaryocytic cell line UT-7. Wild-type UT-7 cells secreted 27/42 cytokines measured. UT-7 clones expressing 50% or 75% JAK2V617F were generated, in which the production of IL-1β, IP-10 and RANTES was increased; other cytokines were not affected. Secondly, we searched for causes of chronic inflammation in MPNs other than driver mutations. Since antigen-driven selection is increasingly implicated in the pathogenesis of blood malignancies, we investigated whether proinflammatory glucosylsphingosine (GlcSph) may play a role in MPNs. We report that 20% (15/75) of MPN patients presented with anti-GlcSph IgGs, distinguished by elevated levels of 11 cytokines. In summary, only IL-1β and IP-10 were linked to JAK2V617F both in patients and in UT-7 cells; other inflammation-linked cytokines in excess in MPNs were not. For subsets of MPN patients, a possible cause of inflammation may be auto-immunity against glucolipids.
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Ma, Wanlong, Hagop Kantarjian, XI Zhang, Xiuqiang Wang, Zhong Zhang, Chen-Hsiung Yeh, Anthony Sferruzza, Susan O'Brien, and Maher Albitar. "Splice Variant JAK2 Transcript Deleting Exon 14 in Patients with Chronic Myeloproliferative Neoplasms." Blood 114, no. 22 (November 20, 2009): 2161. http://dx.doi.org/10.1182/blood.v114.22.2161.2161.
Full textAbstract:
Abstract Abstract 2161 Poster Board II-138 The JAK2 V617F mutation in exon 14 is the most common mutation in chronic myeloproliferative neoplasms (MPNs). While other point mutations and small deletions and insertions in exons 12, 13, and 14 have been reported in the JAK2 JH2 domain, deletion of the entire exon 14 is rarely detected in patients with MPNs. In a series of >10,000 samples from patients with suspected MPNs tested for JAK2 mutations by direct sequencing of mRNA, we detected a complete exon 14 (88 bp) deletion mutation in <1% of those with JAK2 mutation. This appears to be an alternative splicing mutation, not detectable with DNA-based testing, leading to a frameshift deletion in the JAK2 JH2 domain and the expression of a truncated protein (S593I fsX8). Although this mutation was present at detectable levels (>15% of total JAK2 transcript) in a small proportion of MPN cases, we decided to investigate the possibility it may be expressed at low levels (<15% of JAK2 transcript) in patients with MPNs. Using a sensitive reverse transcription-PCR—based fluorescent fragment analysis method to quantify the percentage of truncated (minus exon 14) JAK2 mRNA as compared to wild-type, we tested 61 patients with confirmed MPN; 183 patients with suspected MPNs (93 V617F positive, 90 V617F negative); and 46 healthy normal control subjects. The wild-type PCR product was 273 bp, while the exon 14 splice mutant displayed a 185-bp peak. All samples with a splicing mutant expression to wild-type ratio >15% were confirmed by direct sequencing. The JAK2 exon 14 splice mutation was detected at low levels in 9 of the 61 MPN patients (15%), accounting for 3.96% to 33.85% (mean=12.04%) of JAK2 transcript in these individuals. Among the 183 suspected MPN patients, the exon 14 splice variant was detected in 20 of the 93 (21.5%) with V617F (mean expression level relative to wild type=5.41%, range=2.13%-26.22%) and 31 of the 90 (34.4%) without V617F (mean expression=3.88%; range=2.08%-12.22%). All 46 normal individuals were considered negative for the alternatively spliced transcript. In conclusion, the expression of an alternatively spliced JAK2 mRNA with deletion of exon 14, leading to a truncated JAK2 protein, is a common abnormality in patients with MPNs. This alternatively spliced transcript is more common in MPN patients without V617F mutation and might contribute to the leukemogenesis in these patients. Low levels of JAK2 exon 14 splice mutation may also contribute to the effects of the V617F mutation in patients with MPNs. However, this mutation is missed if DNA and not the RNA is used for testing for JAK2 mutations. Disclosures: No relevant conflicts of interest to declare.
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Landgren, Ola, Lynn R. Goldin, Sigurdur Y. Kristinsson, Elin A. Helgadottir, Jan Samuelsson, and Magnus Björkholm. "Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24 577 first-degree relatives of 11 039 patients with myeloproliferative neoplasms in Sweden." Blood 112, no. 6 (September 15, 2008): 2199–204. http://dx.doi.org/10.1182/blood-2008-03-143602.
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Abstract Previous small studies have reported familial clustering of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We identified 6217 PV, 2838 ET, 1172 MF, and 812 MPN unclassifiable (NOS) patients diagnosed in Sweden, 43 550 controls, and first-degree relatives of cases (n = 24 577) and controls (n = 99 542). Using a marginal survival model, we calculated relative risks (RRs) and 95% confidence intervals as measures of familial aggregation. Relatives of MPN patients had significantly increased risks of PV (RR = 5.7; 3.5-9.1), ET (RR = 7.4; 3.7-14.8), and MPN NOS (RR = 7.5; 2.7-20.8). Analyses stratified by type of first-degree relative revealed consistently higher risks for siblings, compatible with a model of recessive genetic inheritance, which can be confirmed only by identifying the susceptibility gene(s). Mean age at MPN diagnosis was not different (P = .20) for affected relatives of cases (57.5 years) versus controls (60.6 years), and risk of MPN by age was not different for parents versus offspring of MPN cases (P = .10), providing no support for anticipation. Relatives of MPN patients had a borderline increased risk of chronic myeloid leukemia (CML; RR = 1.9; 0.9-3.8; P = .09). Our findings of 5- to 7-fold elevated risk of MPNs among first-degree relatives of MPN patients support the hypothesis that common, strong, shared susceptibility genes predispose to PV, ET, MF, and possibly CML.
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Wang, Steven, Jie Yan, Guangde Zhou, Rebecca Heintzelman, and J. Steve Hou. "Myeloproliferative Neoplasm or Reactive Process? A Rare Case of Acute Myeloid Leukemia and Transient Posttreatment Megakaryocytic Hyperplasia with JAK-2 Mutation." Case Reports in Hematology 2016 (2016): 1–5. http://dx.doi.org/10.1155/2016/6054017.
Full textAbstract:
Myeloproliferative neoplasms (MPNs) are hematopoietic malignancies characterized by unchecked proliferation of differentiated myeloid cells. The most common BCR-ABL1-negative MPNs are polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The discovery of JAK2 V617F mutation has improved our understanding of the molecular basis of MPN. The high frequency of JAK2 mutation in MPN makes JAK2 mutation testing an essential diagnostic tool and potential therapeutic target for MPN. Here, we present a rare case of a 34-year-old patient who was initially diagnosed with acute myeloid leukemia (AML) with mutated NPM1. After chemotherapy treatment followed by granulocyte colony stimulating factor administration, the patient achieved complete remission of AML. However, the bone marrow showed hypercellularity with granulocytic hyperplasia, markedly increased atypical megakaryocytes (50.2/HPF) with focal clustering, and reticulin fibrosis (3/4). JAK2 V617F mutation was also detected. Considering the possibility of AML transformed from a previous undiagnosed MPN, patient underwent peripheral blood allogenic stem cell transplant. This case illustrates the diagnostic challenges of firmly establishing a diagnosis between similar, but distinct, disease entities and an accurate clinicopathological differentiation is crucial.
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Patriarca, Andrea, Donatella Colaizzo, Gianluca Tiscia, Raffaele Spadano, Silvia Di Zacomo, Antonio Spadano, Ida Villanova, Maurizio Margaglione, Elvira Grandone, and Alfredo Dragani. "TET2 Mutations in Ph-Negative Myeloproliferative Neoplasms: Identification of Three Novel Mutations and Relationship with Clinical and Laboratory Findings." BioMed Research International 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/929840.
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High-throughput DNA sequence analysis was used to screen for TET2 mutations in peripheral blood derived DNA from 97 patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). Overall six mutations in the coding region of the gene were identified in 7 patients with an overall mutational frequency of 7.2%. In polycythemia vera patients (n=25) 2 mutations were identified (8%), and in those with essential thrombocythemia (n=55) 2 mutations (3.6%); in those with unclassifiable MPN (n=8) 3 mutations (37.5%). No primary myelofibrosis patients (n=6) harboured TET2 mutations. Three unreported mutations were identified (p.P177fs, p.C1298del, and p.P411del), the first two in patients with unclassifiable MPN, the last in a patient with essential thrombocythemia. On multivariate analysis the diagnosis of an unclassifiable MPN was significantly related to the presence of TET2 mutations (P=0.02; OR: 2.81; 95% CI 1.11–7.06). We conclude that TET2 mutations occur in both JAK2 V617F-positive and -negative MPNs and are more frequent in MPN-U patients. This could represent the biological link between the different classes of myeloid malignancies.
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Srour, Samer A., Susan S. Devesa, Lindsay M. Morton, David P. Check, Rochelle E. Curtis, Martha S. Linet, and Graca M. Dores. "Incidence and Patient Survival of Myeloproliferative Neoplasms (MPNs) and Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs) in the United States: A Population-Based View of the Modern Diagnostic Era." Blood 126, no. 23 (December 3, 2015): 2806. http://dx.doi.org/10.1182/blood.v126.23.2806.2806.
Full textAbstract:
Abstract Introduction: Epidemiologic information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population-based studies. Further, descriptive data encompassing the era of the World Health Organization classification (WHO) of hematopoietic neoplasms and JAK2 V617 mutation testing are sparse. Therefore, we utilized population-based data to comprehensively assess incidence and patient survival of MPNs and MDS/MPNs in the United States (US) during 2001-2012. Methods: Using data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program (SEER) Program, we assessed the incidence rates (IRs), IR ratios (IRRs), and 95% confidence intervals (CI) for each MPN and MDS/MPN entity. We assessed IRs overall and according to sex, race/ethnicity, calendar year of diagnosis, and method of diagnostic confirmation. We utilized the SEER*Stat Survival Session to calculate 5-year relative survival (RS) and 95% CI for each disease entity overall and according to sex and age at diagnosis. Results: A total of 44,912 patients were diagnosed with MPNs and MDS/MPNs during 2001-2012. IRs were highest for polycythemia vera (PV) (n=10,812; IR=10.9 per 1,000,000 person-years) and essential thrombocythemia (ET) (n=9,394; IR=9.6). Except for ET and mastocytosis, the overall IRs for all entities were significantly higher among males than females, with male-to-female IRRs ranging from 1.4-2.3. PV incidence peaked in 2003-2004 and progressively decreased thereafter in contrast to IRs for ET which markedly increased after 2003-2004, with a suggestion of decrease after 2008. BCR-ABL1-positive chronic myelogenous leukemia (CML) IRs increased progressively over the study period while CML, NOS decreased over the study decade. All evaluable MPNs were associated with lower IRs among Hispanic whites than non-Hispanic whites (NHWs), with the exception of BCR-ABL1-positive CML, chronic eosinophilic leukemia (CEL), and juvenile myelomonocytic leukemia which occurred similarly among both groups. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN-unclassifiable, and CEL IRs were 18%, 19%, and 60% higher, respectively, among blacks than NHWs. Among males and females, for all evaluable MPNs and MDS/MPNs, five-year RS was more favorable for younger (<60 years) than older (>60 years) individuals. Patients with PV or ET had the most favorable RS among both sexes and age groups, ranging from 92.0%-96.7% among those <60 years and 79.1%-87.9% among those >60 years. Patients with chronic neutrophilic leukemia, chronic myelomonocytic leukemia, and atypical BCR-ABL1 -negative CML patients had the least favorable 5-year RS (<35%). Females generally had more favorable survival than males, except for older males with PV who had significantly better survival than older women (RS IRR=1.08, 95%CI=1.03-1.13). Conclusion: MPNs are a heterogeneous group of diseases and varying age, sex, and racial/ethnic incidence patterns support distinct etiologies and/or susceptible populations. The introduction of JAK2 V617 mutation testing in 2005 may have had a differential impact on IRs of PV and ET. Less favorable RS among older ages for all MPN subtypes suggests the need for inclusion of these individuals in clinical trials as new treatments become available. Disclosures No relevant conflicts of interest to declare.