Academic literature on the topic 'Ph-negative chronic myeloproliferative neoplasms'
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Journal articles on the topic "Ph-negative chronic myeloproliferative neoplasms"
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Bittencourt, Rosane Isabel, Jose Vassallo, Maria de Lourdes Lopes Ferrari Chauffaille, Sandra Guerra Xavier, Katia Borgia Pagnano, Ana Clara Kneese Nascimento, Carmino Antonio De Souza, and Carlos Sergio Chiattone. "Philadelphia-negative chronic myeloproliferative neoplasms." Revista Brasileira de Hematologia e Hemoterapia 34, no. 2 (2012): 140–49. http://dx.doi.org/10.5581/1516-8484.20120034.
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Ryabukhina, Yu E., P. A. Zeynalova, O. I. Timofeeva, F. M. Abbasbeyli, T. V. Ponomarev, N. A. Kupryshina, and A. G. Zhukov. "Combination approach to diagnosis and treatment of an elderly patient with chronic Ph-negative myeloproliferative neoplasm and concomitant surgical pathology. Clinical observation." MD-Onco 1, no. 1 (December 6, 2021): 61–65. http://dx.doi.org/10.17650/2782-3202-2021-1-1-61-65.
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Chronic myeloproliferative neoplasms (CMPN), Ph-negative, are of clonal nature, develop on the level of hematopoietic stem cell and are characterized by proliferation of one or more hematopoietic pathways. Currently, the group of Ph-negative CMPN includes essential thrombocythemia, primary myelofibrosis, polycythemia vera, myeloproliferative neoplasm unclassifiable.Identification of mutations in the Jak2 (V617F), CALR, and MPL genes extended understanding of biological features of Ph-negative CMPN and improved differential diagnosis of myeloid neoplasms. Nonetheless, clinical practice still encounters difficulties in clear separation between such disorders as primary myelofibrosis, early-stage and transformation of essential thrombocythemia into myelofibrosis with high thrombocytosis. Thrombocytosis is one of the main risk factors for thromboembolic complications, especially in elderly people.A clinical case of an elderly patient with fracture of the left femur developed in the context of Ph-negative CMPN (myelofibrosis) with high level of thrombocytosis is presented which in combination with enforced long-term immobilization and presence of additional risk created danger of thrombosis and hemorrhage during surgery and in the postoperative period.
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Polushkina, Lyubov, Irina Martynkevich, Vasily Shuvaev, Ekaterina Petrova, Lyudmila Martynenko, Natalya Cybakova, Marina Ivanova, et al. "Genetic and Epigenetic Alterations of Ph-Negative Myeloproliferative Neoplasms." Blood 124, no. 21 (December 6, 2014): 5549. http://dx.doi.org/10.1182/blood.v124.21.5549.5549.
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Abstract Objectives and background: Genetic mutations result in abnormalities of myelopoietic proteins and lie in the basis of Ph-negative myeloproliferative neoplasms (MPNs) development and its subsequent progression. Several somatic mutations in JAK2, MPL, TET2, EZH2, ASXL1, CBL, IDH1, IDH2, IKZF1 genes were detected in chronic and blastic phase MPNs. Recent studies have revealed a number of epigenetic alterations that contribute to Ph-negative MPNs pathogenesis and determine the clinical outcome. Mutations involving the EZH2 gene are thought to result in loss of methyltransferase activity suggesting a potential role of tumor suppressor gene silencing as a mechanism in the disease progression. Decrease in ubiquitin ligase activity caused by mutations CBL gene leads to myeloid proliferation. EZH2, CBL mutations are thought to be of prognostic value in MPN’s at the time of transformation to the blastic phase but data are inconsistent and require the further verification.The goal of our research was to determine the significance of mutations genes EZH2, CBL in the diagnosis and prognosis of Ph-negative MPNs. Methods. We have examined 102 patients with Ph-negative MPNs (45 pts with PV, 30 pts with ET and 27 pts with PMF). For all patients the detection of V617F mutation of JAK2 gene was done. V617F-negative pts with PV and pts with ET or PMF underwent the analysis of mutations in 12-th exon of JAK2 and 515 codone of MPL gene respectively. For 80 pts (30 with PV, 28 with ET and 22 with PMF) cytogenetic analysis and EZH2 mutation status were performed. Identification of CBL mutations was performed in 24 patients with available RNA samples. Mutations in 8, 10, 17, 18, 19 exons of EZH2 and RING-domen of CBL were defined by sequence analysis. V617FJAK2 mutation was detected in 44/45 (97,8%) pts with PV, 16/30 (53,3%) pts with ET and 13/27 (48,1%) pts with PMF. 538-539del-insL in 12-th exon of JAK2 was found in 1/45 (2,22%) patient with PV. W515KMPL mutation was identified in 1/30 (3,33%) pt with ET and 1/27 (3,7%) pt with PMF. 2 mutations of EZH2 gene have been found in 2 individuals with PMF (2/22). Both mutations are located in the 19 exon. The Ile713Thr mutation was detected in the patient with a del(6)(q15) karyotype which is associated with an intermediate cytogenetics risk. This patient subsequently underwent transformation from PMF to myelodysplastic syndrome in 9 months after the disease onset. Another case of mutation harboring (Thr731Asp) was detected in a patient with PMF and poor prognosis karyotype (chromosome 7 monosomy). This patient had transformation PMF to acute myeloid leukemia and died after 20 months. Homozygous mutation Q420R in CBL gene was detected in 1/24 patient with complex karyotype. Disease progression was observed after 16 months from the diagnosis. Conclusion. Mutations in EZH2 and CBL genes could be assessed as additional prognostic markers of unfavourable prognosis in patients with BCR-ABL-negative MPNs with different chromosomal aberrations. The integration of cytogenetic and molecular analyses could be a valuable option for stratification of patients and optimising the treatment strategy. References: Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 2010; 24:1128–1138. Disclosures No relevant conflicts of interest to declare.
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Lindholm Sørensen, Anders, and Hans Carl Hasselbalch. "Smoking and philadelphia-negative chronic myeloproliferative neoplasms." European Journal of Haematology 97, no. 1 (October 13, 2015): 63–69. http://dx.doi.org/10.1111/ejh.12684.
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Nann, Dominik, and Falko Fend. "Synoptic Diagnostics of Myeloproliferative Neoplasms: Morphology and Molecular Genetics." Cancers 13, no. 14 (July 14, 2021): 3528. http://dx.doi.org/10.3390/cancers13143528.
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The diagnosis of a myeloid neoplasm relies on a combination of clinical, morphological, immunophenotypic and genetic features, and an integrated, multimodality approach is needed for precise classification. The basic diagnostics of myeloid neoplasms still rely on cell counts and morphology of peripheral blood and bone marrow aspirate, flow cytometry, cytogenetics and bone marrow trephine biopsy, but particularly in the setting of Ph− myeloproliferative neoplasms (MPN), the trephine biopsy has a crucial role. Nowadays, molecular studies are of great importance in confirming or refining a diagnosis and providing prognostic information. All myeloid neoplasms of chronic evolution included in this review, nowadays feature the presence or absence of specific genetic markers in their diagnostic criteria according to the current WHO classification, underlining the importance of molecular studies. Crucial differential diagnoses of Ph− MPN are the category of myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement of PDGFRA, PDGFRB or FGFR1, or with PCM1-JAK2, and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). This review focuses on morphological, immunophenotypical and molecular features of BCR-ABL1-negative MPN and their differential diagnoses. Furthermore, areas of difficulties and open questions in their classification are addressed, and the persistent role of morphology in the area of molecular medicine is discussed.
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Cazzola, Mario, Luca Malcovati, and Rosangela Invernizzi. "Myelodysplastic/Myeloproliferative Neoplasms." Hematology 2011, no. 1 (December 10, 2011): 264–72. http://dx.doi.org/10.1182/asheducation-2011.1.264.
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Abstract According to the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, myelodysplastic/myeloproliferative neoplasms are clonal myeloid neoplasms that have some clinical, laboratory, or morphologic findings that support a diagnosis of myelodysplastic syndrome, and other findings that are more consistent with myeloproliferative neoplasms. These disorders include chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (BCR-ABL1 negative), juvenile myelomonocytic leukemia, and myelodysplastic/myeloproliferative neoplasms, unclassifiable. The best characterized of these latter unclassifiable conditions is the provisional entity defined as refractory anemia with ring sideroblasts associated with marked thrombocytosis. This article focuses on myelodysplastic/myeloproliferative neoplasms of adulthood, with particular emphasis on chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts associated with marked thrombocytosis. Recent studies have partly clarified the molecular basis of these disorders, laying the groundwork for the development of molecular diagnostic and prognostic tools. It is hoped that these advances will soon translate into improved therapeutic approaches.
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Shuvaev, Vasily, Irina Martynkevich, Alla Abdulkadyrova, Vera Udaleva, Tatyana Zamotina, Mikhail Fominykh, Regina Golovchenko, et al. "Ph-Negative Chronic Myeloproliferative Neoplasms – Population Analysis, a Single Center 10-years’ Experience." Blood 124, no. 21 (December 6, 2014): 5556. http://dx.doi.org/10.1182/blood.v124.21.5556.5556.
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Abstract Objectives and background. Nowadays chronic myeloproliferative neoplasms (MPN) other than chronic myelogenous leukemia undergo renaissance of interest. It results from advances in decryption of molecular mechanisms of pathogenesis and invention of target drugs. Epidemiological information is needed to assess potential effect and additional costs of new diagnostic and therapeutic techniques. The objective of our study was to review experience of MPN diagnostic and treatment in our center for past ten years. Methods. Our institution serves as primary hematological outpatient department for a half of Saint-Petersburg city with about 2 million inhabitants. We reviewed patients' charts to obtain information about incidence, symptoms, diagnostic test results, treatment options and relationship to prognostic factors. Statistical methods included descriptive statistics, nonparametric ANOVA for frequencies comparisons and Kaplan-Meyer method with log-rank test for survival comparisons in Statistica 7.0 package. Results. Since 2004 to 2013 there were 570 newly diagnosed MPN patients (pts) in our center. This group consisted of primary myelofibrosis (PMF) (203 pts; 126 female, 77 male; median age 63 years, range 16-83 years), essential thrombocythemia (ET) (201 pts; 146 female, 55 male; median age 58 years, range 23-78 years), polycythemia vera (PV) (166 pts; 96 female, 70 male; median age 57 years, range 20-85 years). The incidence rates were stable during study period: PMF incidence varied from 0.65 to 1.35 with mean of 1.01 new patient per 100 000 inhabitants per year; ET had incidence from 0.60 to 2.1 with mean of 1.00 and PV had incidence from 0.5 to 1.15 with mean of 0.83. The most prevalent symptoms of disease were: splenomegaly (65.5%), constitutional symptoms (fever, night sweats, weight loss) (31.0%), anemia (36.3%) thrombosis (24.1%) for PMF; fatigue (33.2%), headache and dizziness (25.6%), arthralgia (21.8%), erythromelalgia (15.8%) for ET; plethora (82.5%), headache and dizziness (52.4%), fatigue (31.3%) for PV. JAK2V617F was detected in 49.7% of PMF pts, 57.8% of ET pts and in 97.7% of PV pts. Thrombosis rates according WHO IPSET-thrombosis system risks` groups of ET and PV pts were: low-risk group 3.33% (3/90), intermediate-risk group 11.1% (13/117) and 39.4% (63/160) in high-risk group with highly significant (p<0.0001) differences between risks' groups. There were 169 lethal outcomes in the analysed group (102 PMF; 31 ET; 36 PV). Ten-years overall survival rates were 49.8% in PMF pts, 84.6% in ET pts and 78.3% in PV pts. (fig.1). Overall survival in PMF was significantly influenced by risk stratification as IPSS, DIPSS and DIPSS+. Survival curves according DIPSS+ groups are presented in fig.1. Conclusions. Patients with MPN are presented in substantial number; therefore need much finance for novel therapy introduction. Risk stratification systems has high predictive value. Innovative drugs treatment results should be evaluated in comparison with historical control. Figure1 Overall survival in PMF patients according to DIPPS+ stratification groups. Figure1. Overall survival in PMF patients according to DIPPS+ stratification groups. Disclosures No relevant conflicts of interest to declare.
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Santos, Fabio P. S., Renato D. Puga, Ricardo Helman, Welbert Oliveira Pereira, Tarcila S. Datoguia, Bianca Lisboa, Mariana Miyagi, et al. "Whole Exome Sequencing of Philadelphia-Negative (Ph-negative) Myeloproliferative Neoplasms (MPNs) and Myelodysplastic/Myeloproliferative Disorders (MDS/MPD)." Blood 124, no. 21 (December 6, 2014): 4593. http://dx.doi.org/10.1182/blood.v124.21.4593.4593.
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Abstract Introduction: The development of next-generation sequencing has made it feasible to interrogate the entire genome or exome (coding genome) in a single experiment. Accordingly, our knowledge of the somatic mutations that cause cancer has increased exponentially in the last years. MPNs and MDS/MPD are chronic myeloid neoplasms characterized by an increased proliferation of one or more hematopoietic cell lineages, and an increased risk of transformation to acute myeloid leukemia (AML). MPNs and MDS/MPDs are heterogenous disorders, both in clinical presentation and in prognosis. We sought to determine the genetic landscape of Ph-negative MPNs and MDS/MPD through next-generation sequencing. Methods: Paired DNA (sorted CD66b-granulocytes/skin biopsy) from 102 patients with MPNs or MDS/MPD was subjected to whole exome sequencing on a Illumina HiSeq 2000 platform using Agilent SureSelect kit. Diagnosis included primary myelofibrosis (MF; N=42), essential thrombocythemia (ET; N=28), polycythemia vera (PV; N=12), chronic myelomonocytic leukemia (CMML; N=10), systemic mastocytosis (MS; N=6), MDS/MPD-Unclassified (N=2) and post-MPN AML (N=2). Tumor coverage was 150x and germline coverage was 60x. Somatic variants calls were generated by combining the output of Somatic Sniper (Washington University), Mutect (Broad Institute) and Pindel (Washington University). The combined output of these 3 tools was further filtered by in-house criteria in order to reduce false-positive calls (minimum coverage at both tumor/germline ≥8 reads; fraction of reads supporting alternate allele ≥10% in tumor and ≤10% in germline; ratio of allele fraction tumor:germline >2; excluding mutations seen in SNP databases). All JAK2 and CALR mutations were validated through Sanger sequencing. Validation of other somatic mutations is currently underway. Analysis of driver mutations was made with the Intogen web-based software, using the Oncodrive-FM and Oncodrive-cluster algorithms (www.intogen.org). Significantly mutated genes were considered as those with a q-value of <0.10. Results: We identified a total of 309 somatic mutations in all patients, with each patient having an average of 3 somatic abnormalities, fewer than most solid tumors that have been sequenced so far. Mutations occurred in 166 genes, and 40 of these were recurrently somatically mutated in Ph-negative MPNs. By the Oncodrive-FM algorithm, the following genes were identified as the most significantly mutated driver genes in Ph-negative MPNs and MDS/MPDs (in order of significance): CALR, ASXL1, JAK2, CBL, DNMT3A, U2AF1, TET2, TP53, RUNX1, EZH2, SH2B3 and KIT. By the Oncodrive-cluster algorithm, which considers clustering of mutations at a hotspot, the following genes were significantly mutated: KIT, JAK2, SRSF2 and U2AF1. Somatic mutations were seen in genes that are mutated at a low frequency in Ph-negative MPNs, including ATRX, BCL11A, BCORL1, BIRC5, BRCC3, CSF2RB, CUX1, IRF1, KDM2B, ROS1 and SUZ12. Consistent with the clinical phenotype, 96 patients (94%) had mutations that lead to increased cellular proliferation, either through activation of the JAK-STAT pathway (e.g. JAK2, CALR) or mutations that activated directly or indirectly signaling by receptor tyrosine kinases (e.g. FLT3, KIT, CBL). Besides biological pathways regulating cell proliferation, the most commonly implicated pathways included regulation of DNA methylation (e.g. DNMT3A, TET2), mRNA splicing (e.g. U2AF1, SRSF2) and histone modifications (e.g. ASXL1, EZH2), seen in 27%, 25% and 22% of patients, respectively. Abnormalities in these 3 pathways were more often seen in MF, MDS/MPD and CMML, as compared to PV and ET (65% vs. 20%; p<0.0001). Conclusions: Our study represents one of the largest series of patients with these neoplasms evaluated by whole exome sequencing, and together with the published data helps to delineate the genomic landscape of Ph-negative MPNs and MDS/MPDs. The majority of the most frequent mutations seen in Ph-negative MPNs have already been reported. Nevertheless, there are several low frequency mutations that need to be further studied and functionally validated in vitro and in vivo for a deeper knowledge of the pathophysiology of MPNs. Besides activation of cellular proliferation, abnormalities of DNA methylation, histone modification and mRNA splicing emerge as the most important biological pathways in these disorders. Disclosures No relevant conflicts of interest to declare.
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Alati, Caterina, Bruno Martino, Antonio Marino, Francesca Ronco, Manuela Priolo, and Francesco Nobile. "Familial Chronic Myeloproliferative Neoplasms." Blood 116, no. 21 (November 19, 2010): 3078. http://dx.doi.org/10.1182/blood.v116.21.3078.3078.
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Abstract Abstract 3078 Chronic myeloproliferative neoplasms (CMNs) include Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). So far limited studies of familial clusters of CMNs have been reported.Familial chronic myeloproliferative neoplasms are defined when in the same pedigree at least two relatives have CMNs. Familial CMNs should be distinguished from inherited disorders with Mendelian transmission, high penetrance and polyclonal haematopoiesis named ‘hereditary erythrocytosis' and ‘hereditary thrombocytosis'. Recently a 5- to 7-fold higher risk of MPN among first-degree relatives of patients with MPNs was reported. These findings support the limited studies suggesting a familial clustering in MPNs. The analysis of mutations of JAK2 and MPL may improve our ability to identify these conditions. In a consecutive series of patients observed in our Institution from January 2000 to June 2010, we found that among 460 patients with sporadic CMNs and 94 Ph1 positive chronic myeloid leukemia (CML), the prevalence of familial cases was 4%.With 22 pedigrees, 44 patients (8%) were identified with two relatives affected. Familial CMNs were 11 PV,14 ET,7 PMF, 5 CML respectively, while sporadic cases were 96 PV,204 ET,115 PMF and with other 45 CMNS not furtherly classified. As far as the distribution of the different CMNs within the familial cluster, We observed that only in 4 of 22 families (18%) all the affected relatives were diagnosed with the same disease (homogeneous pattern: PV one family and ET three families), whereas 14 families exhibited a mixed distribution among PV, ET and PMF. 8 families exhibited CMNs associated with other hematological disease such as chrocic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodisplastic syndrome (MDS). Among this, 6 families presented a first or second degree of relationship of first and second generation. In 10 cases the relatives were brothers, affected by familial CMNs with a prevalence of PV and TE clinical phenotype at diagnosis.According to JAK2 (V617F) mutational status, analyzed in 30 out of 44 patients, 19 patients showed a positivity pattern, while 18 families showed a heterogeneous pattern; they included both JAK2 (V617F) -positive and JAK2 (V617F)-negative patients. Among the 19 patients with JAK2 (V617F) positivity, the distribution of positivity according to the diagnosis was 100% of PV, 45% of ET and 55%of PMF; homozygosity was present only in PV cases. In our series, only two members of the same family were affected by familial CMNs. Finally it should be noted that in our series of familial cases clinical presentation, therapeutic approach and type and severity of complications were comparable to that of sporadic cases. In conclusion, the present study indicates the relevant possibility of familial CMNs, thus suggesting the opportunity of a detailed family history as part of the initial work-up of patients with CMDs; in addition it also suggests the usefulness of an accurate biological study. Disclosures: No relevant conflicts of interest to declare.
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Jager, R., and R. Kralovics. "Molecular Pathogenesis of Philadelphia Chromosome Negative Chronic Myeloproliferative Neoplasms." Current Cancer Drug Targets 11, no. 1 (January 1, 2011): 20–30. http://dx.doi.org/10.2174/156800911793743628.
Full textDissertations / Theses on the topic "Ph-negative chronic myeloproliferative neoplasms"
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MINNUCCI, GIULIA. "Development and clinical validation of a novel and NON-PCR based method for the detection of the JAK2V617F mutation in chronic mycloproliferative neoplasms." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/29394.
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Myeloproliferative Neoplasms (MPNs) are haematologic disorders of myeloid progenitor cells characterized by the frequent presence of an acquired activating mutation in exon 14 of the Janus kinase 2, consisting in a Valine to Phenilalanine substitution at codon 617 (JAK2V617F). The kinase activity of mutated JAK2 is constitutively activated, inducing uncontrolled cell proliferation and resistance to apoptosis. JAK2V617F is found in 95% of Polycythemia Vera (PV), 50% of Idiopathic Myelofibrosis (IMF), and 20-40% of Essential Thrombocythemia (ET), the three diseases belonging to MPNs, as described in the World Health Organization (WHO) classification (REF). Thus, the JAK2V617F mutation represents the key clonal marker for diagnosis of MPNs. The identification of the JAK2V617F is mandatory in the diagnostic work up of PV, ET, and IMF. Several molecular techniques are currently available but each of them presents some limits.
We developed a novel non-PCR molecular method for the identification of the JAK2V617F mutation based on an Allele Specific-Loop mediated AMPlification (AS-LAMP). This innovative technique amplifies DNA targets under isothermal conditions with high specificity, efficiency, and rapidity. The method neither requires a thermal cycler equipment nor gel separation and the DNA amplification reaction is visible to the naked eye, monitorable by turbidimetry and fluorescence.
This method was validated on DNA from both cell lines as well as patients with chronic myeloproliferative neoplasms. Results were compared with those obtained by conventional PCR methods.
The AS-LAMP allows a rapid and robust identification of DNA samples harboring the JAK2V617F mutation. No false positive or false negative results were registered on clinical samples previously tested by the reference assay ASO-PCR. This new assay proved also remarkably sensitive since the mutated JAK2V617F DNA could be detected down to 0.05% on clinical samples.
AS-LAMP is a simple, robust and easily applicable tool for the molecular diagnosis and monitoring of JAK2V617F mutation in chronic myeloproliferative neoplasms.
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Perricone, Margherita <1987>. "Characterization of Philadelphia-negative Chronic Myeloproliferative Neoplasms: identification of novel biomarkers by Next Generation Sequencing and study of interactions between hematopoietic stem cell and the inflammatory cell micro-environment." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2018. http://amsdottorato.unibo.it/8358/1/PhD%20Thesis_MPerricone_final.pdf.
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Myeloproliferative Neoplasms (MPN) are a heterogeneous group of hematological malignancies, consisting in clonal disorders of the hematopoietic stem/progenitor cell (HSC/PC). Molecular alterations and inflammatory microenvironment represent the two main etiopathogenic factors of MPN.
The aim of this study was the molecular characterization of MPN patients and the study of interactions between HSC/PC and the inflammatory cell micro-environment.
We investigated young (<40 years at diagnosis) ET and early-PMF patients, and patients with a JAK2V617F allele burden (AB) <3%, demonstrating that its determination is relevant both at diagnosis and during follow up. Indeed, it allows to prove the presence of a clonal hematopoiesis and, also, to predict clinical outcome. Of note, an AB≥0,8% always corresponds to an overt MPN phenotype. In this context, coordinating a network of 19 Italian laboratories, we identified the ipsogen JAK2 MutaQuant kit as the most sensitive and efficient assay for the quantification of samples with different mutation loads (in particular those with AB≤1%). With regard to the role of inflammatory microenvironment in the pathogenesis of MF, IL-1β and TIMP-1 seemed to confer a survival advantage to MF-derived HSPCs, enhancing their proliferation and in vitro migration, as well as their clonogenic ability. Finally, in this study we tested three different gene panels for mutations detection, obtaining promising results in terms of coverage analysis (more than 95% of target regions with depth greater than 500X) and identifying gene variants with very low mutation load (<1%) in all patients.
In conclusion, this study set the basis for the standardization of molecular techniques for the determination of JAK2V617F AB, and for the validation of a robust NGS approach to be translated into a diagnostic setting. Moreover, IL-1β and TIMP-1 emerged as novel promoting factors of the in vitro maintenance of MF-derived HSPC, which may be exploited as potential targets of therapy.
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Orvain, Corentin. "Elaboration de nouveaux outils pour le diagnostic et le pronostic des patients atteints de syndrome myéloprolifératif. Circulating Cd34+ cell count differentiates primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms: a pragmatic study Sequential mutational evaluation of CALR-mutated myelopro-liferative neoplasms with thrombocytosis reveals an associa-tion between CALR allele burden evolution and diseaseprogression." Thesis, Angers, 2019. http://www.theses.fr/2019ANGE0043.
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Plusieurs scores pronostiques ont été élaboré chez les patients atteints de leucémie myéloïde chronique (LMC) sans qu’un lien n’ait été établi entre ces scores et la biologie de la LMC. Nous montrons que les patients de mauvais pronostic ont une expression accrue de GATA2, en corrélation avec les taux de basophiles et de plaquettes au diagnostic, paramètres utilisés dans le calcul des scores pronostiques, et à l’expression de gènes impliqués dans le fonctionnement des basophiles. Cette expression augmente lors de la transformation sur un versant myéloïde. Alors qu’un certain nombre de patients peuvent désormais tenter un arrêt de traitement avec un succès dans 50% des cas, il apparaît essentiel de revoir notre manière d’évaluer le pronostic. Ainsi, l’obtention d’une réponse moléculaire optimale dès 6 mois est associée avec une tentative ultérieure d’arrêt de traitement dans notre cohorte. Alors que le diagnostic de la LMC est relativement aisé, il est parfois difficile de différencier thrombocytémie essentielle (TE), pré-myélofibrose et myélofibrose. Nous réévaluons l’intérêt de la numération des cellules CD34+ circulantes: un nombre de cellules CD34+ circulantes < 10/μl permet d’exclure le diagnostic de myélofibrose avec une très bonne sensibilité (97%) et spécificité (90%). Dans une cohorte de patients atteints de TE avec mutation CALR, nous montrons que l’augmentation de sa charge allélique, et non la présence de mutations additionnelles, est associée à un risque accru de progression. L’ensemble de ces paramètres sera étudié dans une étude prospective multicentrique visant à établir un score diagnostique non invasif permettant de différencier TE, pré-myélofibrose et myélofibroseVarious scoring systems have been successively elaborated to predict outcome of patients with chronic myeloid leukemia (CML). However, no link has been identified between those scores and CML biology. We show that high-risk patients have high GATA2 levels, in correlation with higher baseline basophil and platelet counts, two parameters used to calculate prognostic scores, and expression of genes involved in basophils. GATA2 expression increases in accelerated and myeloidblast-phase. Since some patients can now stop treatment, with a near 50% success rate, it is necessary to reevaluate the way we assess prognosis. A 6-month optimal molecular response was associated with an increased discontinuation attempt rate in our cohort. While the diagnosis of CML is fairly easy, it is often difficult to distinguish essential thrombocythemia (ET), pre-myelofibrosis and myelofibrosis. The numeration of CD34+ circulating cells is of interest in this setting : we show that a number < 10/μ excludes the diagnosis of myelofibrosis with a very good sensitivity (97%) and good specificity (90%). In a cohort of patients with ET and CALR mutation, We show that an increase in allele burden, and not additional mutations at diagnosis or during follow-up,is associated with an increased risk of progression. All of these parameters will be evaluated in a prospective multicentric study in order to elaborate a non-invasive diagnostic score to distinguish TE, pre-myélofibrosis, and myelofibrosis
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PIERI, LISA. "Study of new molecular alterations on Philadelphia-negative chronic myeloproliferative neoplasms." Doctoral thesis, 2013. http://hdl.handle.net/2158/804681.
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Lo studio si è basato su tecnologia di SNP array per identificare regioni cromosomiche oggetto di alterazioni di copy number in un’ampia casisitica di pazienti con neoplasie mieloproliferative croniche Ph-negative, sia nella fase cronica di malattia sia soprattutto nella transizione ad una leucemia acuta. Sulla base di una di queste anomalie identificate, sono poi state condotte ulteriori ricerche che hanno permesso di identificare una nuova anomalia molecolare, non descritta in precedenza, che genera un trascritto chimerico di fusione che è in avanzata fase di caratterizzazione.
In this study SNP array technology was used to identify chromosomal regions subject to copy number alterations in a wide number of patients with Ph-negative chronic myeloproliferative neoplasms, both in the chronic phase of the disease and in the transition to acute leukemia. On the basis of these first results, further studies were conducted that allow to identified a new molecular defect, not previously described, which generates a chimeric fusion transcript that is in an advanced stage of characterization.
Books on the topic "Ph-negative chronic myeloproliferative neoplasms"
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Steensma, David P. Malignant Hematology. Oxford University Press, 2012. http://dx.doi.org/10.1093/med/9780199755691.003.0296.
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The hematologic neoplasms include lymphoproliferative disorders (eg, chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL], large granular lymphocyte leukemia, hairy cell leukemia [HCL], Hodgkin lymphoma, non-Hodgkin lymphoma), plasma cell disorders (multiple myeloma, light chain amyloidosis, Waldenström macroglobulinemia, POEMS syndrome, heavy chain disease, plasmacytoma), chronic myeloid neoplasms (chronic myeloid leukemia, the BCR/ABL-negative myeloproliferative neoplasms, myelodysplastic syndromes), and acute leukemia (acute myeloid leukemia, acute lymphocytic leukemia). In addition, clonal but not overtly malignant conditions are common in the general population, including monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B lymphocytosis (MBL).
Book chapters on the topic "Ph-negative chronic myeloproliferative neoplasms"
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Tantravahi, Srinivas K., Jamshid S. Khorashad, and Michael W. Deininger. "Genomic landscape of myeloproliferative neoplasms." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 15–31. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0002.
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The discovery of the Philadelphia chromosome (Ph) and BCR-ABL1 fusion gene in chronic myeloid leukaemia (CML) was a first step in understanding the genetic basis of myeloproliferative neoplasms (MPN), but it took more than 20 years until the molecular basis of Ph– MPN was unravelled with the identification of mutually exclusive mutations in JAK2, MPL, and CALR. The common effect of these mutations, activation of JAK/STAT signalling, informed the therapeutic development of JAK kinase inhibitors. Additional mutations in epigenetic modifier, mRNA splicing, and transcriptional regulator genes are present in many MPN cases. Elucidating the prognostic and functional significance of these mutations is the focus of intense ongoing studies. Given that JAK kinase inhibitors have limited impact on the mutant allele burden these additional pathways may offer much needed additional therapeutic targets. In this chapter, we discuss in detail the genetic landscape of MPN in the context of prognostication and therapy.
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Fleischman, Angela G., and Richard A. Van Etten. "Pathogenesis of myeloproliferative neoplasms." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 32–44. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0003.
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The myeloproliferative neoplasms (MPN) were first grouped together by Dameshek in 1951 based upon their similar clinical characteristics. Since that time, and particularly over the past decade, molecular biological and genetic investigation into the pathogenesis of MPN has revealed their shared stem cell nature, a common pathophysiological theme of aberrant cytokine signalling through dysregulated tyrosine kinases that drives the overproduction of maturing myeloid cells, and, as in other myeloid neoplasms, a major modifying role for loss of function mutations in epigenetic regulatory proteins. This chapter reviews the molecular pathogenesis of chronic myeloid leukaemia (CML) and the Philadelphia-negative MPN with a particular emphasis on the contribution of mouse models of MPN to our understanding of these diseases.
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Rambaldi, Alessandro, and Nicholas Kröger. "Stem cell transplantation for BCR-ABL1-positive and negative myeloproliferative neoplasms." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 249–66. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0016.
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The indication to allogeneic stem cell transplantation has changed in the treatment strategy of chronic myeloid leukaemia (CML) and myelofibrosis (MF). The introduction of tyrosine kinase inhibitors has confined the indication to transplant only to the very few CML patients who fail the medical treatment or progress to a blastic phase of the disease. Nonetheless, a distinct group of CML patients still require allogeneic transplant that remains a curable treatment options even for these otherwise incurable patients. On the other hand, the allogeneic transplant activity for myelofibrosis is growing despite the persistent concern about the non-relapse mortality that remains significantly high in most studies and never below 20%. The availability of the new treatment option represented by JAK2 inhibitors hold promise not only for improving the quality of life but also the transplant outcomes of MF patients. However, their use poses new challenges for the most wise and appropriate selection of patients to transplant.
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Najfeld, Vesna. "Conventional and Molecular Cytogenetics of Ph-Negative Chronic Myeloproliferative Disorders." In Myeloproliferative Disorders, 51–68. CRC Press, 2007. http://dx.doi.org/10.3109/9781420061635-3.
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Musteata, Vasile, and Valentina Stratan. "Diagnosis and Management of Chronic BCR-ABL-Positive and BCR-ABL-Negative Myeloproliferative Neoplasms in Elderly Patients: An Approach towards Hematologic Oncology and Public Health." In Issues and Developments in Medicine and Medical Research Vol. 5, 134–41. Book Publisher International (a part of SCIENCEDOMAIN International), 2022. http://dx.doi.org/10.9734/bpi/idmmr/v5/2405c.
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Aruch, Daniel, and Ronald Hoffman. "Thrombocytosis and essential thrombocythaemia." In Oxford Textbook of Medicine, edited by Chris Hatton and Deborah Hay, 5239–47. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0518.
Full textAbstract:
The term thrombocytosis refers to a platelet count elevated above 450 × 109/litre, which can be (1) primary—including essential thrombocythaemia, chronic myeloid leukaemia, polycythaemia vera, and myelodysplastic syndromes; or (2) secondary—including iron deficiency, infection, blood loss, and malignancy. Essential thrombocythaemia: aetiology—the JAK2 V617F missense mutation typical of polycythaemia vera is found in about 50% of cases. In addition, 10% of patients have a mutation in the thrombopoietin receptor gene, MPL, and 30% have a mutation in calreticulin (CALR). Approximately 10% of patients have none of these mutations and are referred to as ‘triple negative’ essential thrombocythaemia. Diagnosis requires all of the following four major criteria: (1) platelet count greater than 450 × 109/litre; (2) bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei without a significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibres; (3) failure to meet the criteria for other myeloproliferative neoplasms; and (4) presence of JAK2, CALR, or MPL mutations. Alternatively, diagnosis can be met when the first three major criteria are present and the one minor criterion, namely the presence of another clonal marker or absence of evidence for reactive thrombocytosis. Treatment requires risk stratification based on the age of the patient and any prior history of thrombosis, with treatment being reserved for those at a high risk of developing complications and not introduced simply on the basis of platelet counts alone unless there is extreme thrombocytosis (>1500 × 109/litre). Therapies include low-dose aspirin and cytoreduction.
Conference papers on the topic "Ph-negative chronic myeloproliferative neoplasms"
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Oh, Stephen T., Jacob M. Zahn, Erin F. Simonds, John Bell, Georges Natsoulis, Jason Buenstro, Carol Jones, et al. "Abstract B6: Identification of novel mutations in the inhibitory adaptor protein LNK in patients with JAK2 V617F-negative and -positive chronic myeloproliferative neoplasms." In Abstracts: AACR International Conference on Translational Cancer Medicine-- Jul 11-14, 2010; San Francisco, CA. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1078-0432.tcmusa10-b6.
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