Role of JAK2 V617F mutation and aberrant expression of microRNA-143 in myeloproliferative neoplasms

2015 ◽  
Vol 53 (7) ◽  
Author(s):  
Marco Benati ◽  
Martina Montagnana ◽  
Elisa Danese ◽  
Giovanna De Matteis ◽  
Dino Veneri ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Blood Cells ◽  
Healthy Subjects ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Idiopathic Myelofibrosis ◽  
Aberrant Expression ◽  
Who 2008

AbstractMyeloproliferative neoplasms (MPNs) are clonal myeloid disorders characterized by the overproduction of mature blood cells. The pathogenetic hallmark of MPNs is the dysregulation of JAK-STAT signaling, usually associated with theIn total 78 patients with a clinical diagnosis of polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IM), made according to the WHO 2008 criteria, were included in the study. Twenty healthy subjects were checked as controls. Quantification ofThe miR-143 expression in MPNs patients was 2.97-fold higher than in controls.Our findings of aberrant miR-143 expression support the concept that factors other than

scholarly journals What are the current treatment approaches for patients with polycythemia vera and essential thrombocythemia?

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 480-488 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Paola Guglielmelli
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
State Of The Art ◽  
Myeloproliferative Neoplasms ◽  
Symptom Burden ◽  
Current Treatment ◽  
Interferon Α ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms

Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom burden, and impaired survival mainly due to thrombosis, progression to myelofibrosis, and transformation to acute leukemia. In this manuscript, we will review the most recent changes in diagnostic criteria, the improvements in risk stratification, and the “state of the art” in the daily management of these disorders. The role of conventional therapies and novel agents, interferon α and the JAK2 inhibitor ruxolitinib, is critically discussed based on the results of a few basic randomized clinical studies. Several unmet needs remain, above all, the lack of a curative approach that might overcome the still burdensome morbidity and mortality of these hematologic neoplasms, as well as the toxicities associated with therapeutic agents.

Direct Activation of STAT5 by TEL-Lyn Fusion Protein Promotes Induction of Myeloproliferative Neoplasms with Myelofibrosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4114-4114
Author(s):  
Yusuke Takeda ◽  
Chiaki Nakaseko ◽  
Hiroaki Tanaka ◽  
Masahiro Takeuchi ◽  
Makiko Yui ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Signaling Molecules ◽  
Janus Kinase ◽  
Idiopathic Myelofibrosis ◽  
Lyn Kinase

Abstract Abstract 4114 Background Myeloproliferative neoplasms (MPN), a group of hematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. The V617F somatic mutation in the Janus kinase 2 (JAK2) gene has recently been found in the majority of patients with polycythemia vera (PV) and more than half of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). The expression of JAK2 V617F causes a PV-like disease with myelofibrosis in a murine bone marrow (BM) transplant model. In addition, a gain-of-function c-MPL W515 mutation was described in nearly 10% of patients with JAK2 V617F-negative IMF. However, the mechanism responsible for MPD and the formation of myelofibrosis in patients without JAK2 or c-MPL mutations is still unclear. We previously identified the fusion of the TEL gene to the Lyn gene (TEL-Lyn) in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of TEL-Lyn into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged Lyn kinase in the pathogenesis of MPN with myelofibrosis. However, the signaling molecules directly downstream from and activated by TEL-Lyn remain unknown. Design and Methods We examined the signaling pathways activated by TEL-Lyn by Western blotting, immunoprecipitation, and in vitro kinase assay using a TEL-Lyn kinase-dead mutant as a control. We further characterized the functional properties of Stat5-deficient HSCs transduced with TEL-Lyn by colony-forming assay and bone marrow transplantation to evaluate the role of STAT5 in TEL-Lyn-induced MPN. Results TEL-Lyn was demonstrated to be constitutively active as a kinase through autophosphorylation. In TEL-Lyn-expressing cells, STAT5, STAT3, and Akt were constitutively activated. Among these signaling molecules, STAT5 was activated most prominently and this occurred without the activation of Jak2, the major kinase for STAT5. TEL-Lyn was co-immunoprecipitated with STAT5, and STAT5 was phosphorylated when incubated with TEL-Lyn, but not with TEL-Lyn kinase-dead mutant. These results indicate that TEL-Lyn interacts with STAT5 and directly activates STAT5 both in vitro and in vivo. Of note, the capacity of TEL-Lyn to support the formation of hematopoietic colonies under cytokine-free conditions in vitro and to induce MPN with myelofibrosis in vivo was profoundly attenuated in a Stat5-null background. Conclusions In this study, we clearly showed that TEL-Lyn directly activates STAT5 and the capacity of TEL-Lyn to induce MPN with myelofibrosis was profoundly attenuated in the absence of STAT5. Our findings of TEL-Lyn in this study support the role of the Src family kinases in the regulation of STAT pathways and implicate active Lyn in the alternative pathway for STAT activation in pathological cytokine signaling. Our mouse model of MPD with myelofibrosis would be beneficial for the analysis of therapeutic approaches for myelofibrosis. Disclosures: No relevant conflicts of interest to declare.

Analysis of JAK2 V617F Mutation and Its Clinical Significance in Patients with Thrombocythemia and Other Myeloproliferative Neoplasms in Chinese

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4687-4687
Author(s):  
Yue Xu ◽  
Changxin Yin ◽  
Han He ◽  
Lingling Shu ◽  
Fuqun Wu ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Jak2 Mutation ◽  
Western Countries ◽  
Arms Pcr ◽  
V617f Mutation

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.

High Percentage of JAK2 exon 12 Mutation in Polycythemia Vera and Essential Thrombocythemia Among Populations of Qatar

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5064-5064
Author(s):  
Mohamed A. Yassin ◽  
Hanadi Rafii El-Ayoubi ◽  
Nader Al-Dewik
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Genomic Dna ◽  
Research Funding ◽  
Mutant Allele ◽  
Jak2 V617f ◽  
Research Fund ◽  
Idiopathic Myelofibrosis ◽  
Essential Thrombocytosis ◽  
High Incidence

Abstract Abstract 5064 The chronic myeloproliferative Neoplasm (NPM) are clonal hematopoietic stem cell malignancies with 3 main subtypes: polycythemia vera (PV), essential thrombocytosis, and idiopathic myelofibrosis. PV is characterized by increased RBC proliferation in the absence of erythropoietin and proliferation of myeloid lineages usually is noted, A gain-of-function mutation of Janus kinase 2 (JAK2) V617F, is identified in about 95% of patients with PV and about 50% of patients with essential thrombocytosis and idiopathic myelofibrosis. It has been shown that JAK2 exon 12 mutations can activate erythropoietin signaling pathways while these findings have been confirmed by many studies from Western countries, there are no reports from Asian countries in general and Arab countries in particular about the prevalence of the JAK2 exon 12 mutation in patients with PV and ET. In the present study, we determined the prevalence of JAK2V617F and JAK2 exon 12 mutations in patients with PV and ET in Qatar. Materials and Methods We enrolled patients with a diagnosis of PV and ET at National Centre for Cancer Care and Research in Qatar from January till June 2012. The diagnosis of PV and ET was established according to the 2008 World Health Organization criteria. The study included 82 patients. Clinical information and the CBC data at diagnosis were obtained from medical records. Pretreatment serum erythropoietin levels. Total DNA was isolated from buffy coat cells taken from peripheral blood using a kit (QIAamp DNA Mini Kit, Qiagen, Hilden, Germany) according to the manufacturer's instructions. Allele-specific polymerase chain reaction (PCR) was performed using 80 ng of genomic DNA as the template in a35-cycle PCR reaction at an annealing temperature of 58°C, as previously described. The mutant allele yields a 203-base-pair (bp) PCR product (sensitivity of mutant allele detection <1%). For exon 12 mutation screening, 80 ng of genomic DNA was amplified by specific primers designed to amplify a region of 453 bp containing the 128 bp of the exon 12 sequence of JAK2. PCR products were directly sequenced in both directions on an ABI 3730 DNA Analyzer using the BigDye Terminator Sequencing kit. Results We examined the occurrence of JAK2V617F and JAK2 exon 12 mutations in a clinical cohort of 82 patients with polycythemia vera (PV) and Essential thrombocythemia (ET) Of which 42 patients had PV aged 25 to 53, 13 (31%) females and 29 (69 %) males and V617F mutation was detected in all of them exon 12 mutation was detected in 38 (90. 47%) patients. We found 2 different exon 12 mutations:3 N542-E543del, 1 F537-K539delinsL, and among 40 ET patients aged 25 to 59, 22 (55 %) males and 18 (45%) females, 35 patients (87. 5%) were JAK2 V617F and JAK 2 exon12 positive and 5 (12. 5%) were JAK2V617F as well as exon 12 negative patients with V617F and exon 12 mutations showed significantly higher WBC and platelet counts at diagnosis than patients with exon V617F mutation alone (P =. 021 and P =. 038, respectively). We report a surprisingly high incidence of exon 12 mutations in MPN patients with PVand ET in Qatar, a result quite different from reports in the Western literature (P =. 001). Conclusion Our data suggest that exon 12 mutation of JAK2 in patients with PV and ET may have an uneven geographic distribution. A clinical laboratory providing the V617F test alone may risk missing a substantial number of patients with PV in areas with a high incidence of exon 12 mutation. the importance of such associations may need further studies and evaluations. Disclosures: Yassin: Qatar National Research Fund: Patents & Royalties, Research Funding. Rafii El-Ayoubi:Qatar National Research Fund: Patents & Royalties, Research Funding. Al-Dewik:Qatar National Research Fund: Patents & Royalties, Research Funding.

Leukocytosis Can Predict Thrombotic Events in Myelofibrosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5191-5191
Author(s):  
Laura Coutinho Vassalli ◽  
Emilia Carolina Malafaia ◽  
Maria L. Chauffaille ◽  
Daniella Kerbauy
Keyword(s):  
Polycythemia Vera ◽  
Blood Cells ◽  
Myeloproliferative Neoplasms ◽  
Thrombotic Event ◽  
White Blood Cells ◽  
Jak2 V617f ◽  
The Other ◽  
Jak2 V617f Mutation ◽  
Increased Risk ◽  
V617f Mutation

Abstract Thrombotic events are the main complication of Philadelphia-negative chronic myeloproliferative neoplasms (MPN). In polycythemia vera (PV) and essential thrombocythemia (ET), risk factors for thrombosis are well established, such as age greater than 60 years and previous thrombosis. However, the role of JAK2 V617F mutation and leukocytosis at diagnosis as risk factor for thrombosis is still controversial. Our aim was to identify factors related to the risk for thrombotic events in the studied population.This study is a retrospective non-interventional cohort. All of the analyses were performed using the database of 142 patients with MPN regularly followed at the Hematology Division (at UNIFESP-SP) from 1992 to 2014. Diagnosis was established according to WHO criteria. We analyzed the JAK2 V617F mutation, hemoglobin (g/dL), hematocrit (%), white blood cells (x109/L) and platelets (x109/L) at the diagnosis and DIPSS-Plus risk score (International Working Group for Myelofibrosis Research and Treatment, 2009). These variables were associated with thrombotic event at any time.Of the 142 patients, 54 had diagnosis of PMF, 28 of PV, 33 of ET and 27 of post-essential thrombocythaemic myelofibrosis (post ET MF) or post-polycythaemic myelofibrosis (post-PV MF). This last group was included in myelofibrosis group for statistical purposes. Thrombotic events were more frequent in PV patients (39.2%), followed by ET (33.3%), and PMF (20.9%). From those which JAK2 mutation was obtained, it was positive in 92.4% of PV patients, 62% of PMF and 50% of ET. In none of the three groups, the presence of JAK2 V617F mutation was related to increased risk of thrombosis. In myelofibrosis, leukocytosis was higher among thrombotic patients (median of 13.7 in thrombotic group versus 9.7x 109/L; p 0.0379). None of the other parameters, hemoglobin, hematocrit, platelets and DIPSS-Plus were statistically significant. In ET, the hemoglobin level at diagnosis was significantly higher in the presence of thrombosis (mean of 14.57 in thrombotic group against 13.03 g/dL in the non-thrombotic one, p 0.0428). The other parameters, hematocrit, white blood cells and platelets were not relevant. The median WBC in the thrombotic group was 9.4 and in the non-thrombotic one 9.3 x109/L. Finally, in polycythemia vera, none of the variables were related to thrombosis. Among the studied population, leukocytosis was increased in patients with thrombotic event in MF. Thus, monitoring leukocyte count in MF is essential to predict thrombosis risk and should be further studied in order to define therapeutic goals in these patients. Disclosures No relevant conflicts of interest to declare.

Clinical Factors Predictive Of Myelofibrotic Evolutions In Patients With Essential Thrombocythemia and Polycythemia Vera

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4082-4082 ◽  
Author(s):  
Mario Tiribelli ◽  
Federico De Marchi ◽  
Daniela Barraco ◽  
Luciana Marin ◽  
Erika Codarin ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Clinical Feature ◽  
Baseline Characteristics ◽  
Wbc Count ◽  
Prognostic Risk Factors

Abstract Introduction Evolution to myelofibrosis (MF) represents a relatively rare but always severe event in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Few reports have focused on the clinical and biological features at diagnosis of ET and PV that correlate with progression to MF. Aims and Methods We retrospectively studied a series of patients with post-ET and post-PV MF and compared with a group of ET and PV patients with a long follow-up without myelofibrotic evolution, with the aim to identify prognostic factors for MF. Forty-three patients with post-ET (n=29) and post-PV (n=14) MF followed at our institution were compared with 125 ET and 75 PV patients with at least 9 years of follow-up without evolution. Diagnosis of ET and PV was confirmed according to WHO criteria (including JAK2 analysis, performed since 2006 and study), evolution to MF was defined according to IWG-MRT proposed criteria. The following parameters, available for all patients at diagnosis of ET or ET, were taken into consideration to find prognostic risk factors for myelofibrosis: age, platelet (PLT) count, hemoglobin (Hb) and hematocrit (Hct) levels, white blood cell (WBC) count. Statistical analyses were conducted using Student t test. Results Median time from diagnosis of ET/PV and progression to MF was 156 months (range: 29-314). Comparing baseline characteristics of patients who evolved to MF and those who did not, we did not found any significant correlation. Mean data at diagnosis for patients with (n = 43) or without (n=200) subsequent evolution to MF were as follow: age 52.1 vs 53.1 years (p=0.79), Hb 15.4 vs 15.7 g/dl (p=0.59), Hct 47.2 vs 47.1% (p=0.67), WBC 9.8 vs 9.1 x 109/l (p=0.11), PLT 713 vs 689 x 109/l (p=0.87). Also when considering only the 29 post-ET MF and the 125 ET patients, there was no clinical feature present at diagnosis that could foresee a future myelofibrotic evolution. Conversely, in the 14 post-PV MF and 75 PV patients, progression to MF was predicted only by higher WBC count (11.4 vs 9.3 x 109/l, p=0.046), while no correlation was found with age, Hb, Hct or PLT [Table 1]. Conclusions Concordant with some previous reports, our data suggest a possible role of leucocytosis as an adverse risk factor for progression to MF in patients with PV, though not in ET. Other clinical characteristics present at diagnosis, such as advanced age, anemia or polycythemia and thrombocytosis do not seem to be associated with higher risk of fibrotic evolution in patients with myeloproliferative neoplasms. Disclosures: No relevant conflicts of interest to declare.

scholarly journals JAK2 V617F prevalence in Brazilian patients with polycythemia vera, idiopathic myelofibrosis and essential thrombocythemia

2007 ◽  
Vol 30 (2) ◽  
pp. 336-338 ◽  
Author(s):  
Bárbara da Costa Reis Monte-Mór ◽  
Anderson Ferreira da Cunha ◽  
Kátia Bórgia Barbosa Pagnano ◽  
Sara Terezinha Saad ◽  
Irene Lorand-Metze ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Idiopathic Myelofibrosis

High Mitochondrial Membrane Potential Identifies Patients with Myeloproliferative Neoplasms with a More Aggressive Natural History

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1992-1992
Author(s):  
Jeffrey R Gardner ◽  
Omar Abdel-Wahab ◽  
Mark Frattini ◽  
Joseph G Jurcic ◽  
Kristina Knapp ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Polycythemia Vera ◽  
Mitochondrial Membrane Potential ◽  
Essential Thrombocythemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Mitochondrial Membrane ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Acute Myeloid

Abstract Abstract 1992 The myeloproliferative neoplasms (MPN) can have a variable natural history. Polycythemia vera and essential thrombocythemia, in particular, are conditions that can extend over decades, but some patients have clinical progression to myelofibrosis or acute myeloid leukemia. As first articulated by Warburg, cancers are metabolically distinguished from normal tissues by the use of glycolysis under aerobic conditions. To metabolically characterize the blood cells of patients with myeloproliferative neoplasms, we measured the mitochondrial membrane potential using the cyanine dye, JC-1. In examining cells derived from the blood and/or marrow of 159 patients with primary myelofibrosis, polycythemia vera and essential thrombocythemia, we found that the mitochondrial membrane potential (FL2/FL1=electrochemical potential/mitochondrial mass) was elevated compared to the blood cells of normal individuals. Thirty five percent of patients with polycythemia vera and essential thrombocythemia had normal MMP. In contrast, 97% of patients with primary myelofibrosis, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis and acute myeloid leukemia following an MPN had evidence of cell populations with higher mitochondrial membrane potential. Cells with distinctly higher mitochondrial membrane potential could be indentified in platelets and polymorphonuclear leukocytes; however the MMP of lymphocytes was normal, indicating that the alteration in metabolic state likely occurred in a multipotential myeloid stem cell. Cell populations were confirmed by co-staining with anti-CD19, -CD45, -GlycophorinA and -β3-integrin antibodies. Sequential analysis of patient samples found that the acquisition of higher mitochondrial membrane potential was stable and persistent over 2 years or more of follow up and that elevated membrane potential predisposed patients to disease progression. The balance of patients (65%) with ET had evidence of increased MMP suggesting the possibility of disease in an early state of evolution to a more aggressive condition. The increased MMP did not correlate with the presence of mutation in JAK2. These results indicate that clinically advanced MPN can be characterized by changes in mitochondrial physiology that might be identified non-invasively by flow cytometric staining with JC-1. In addition, the early nature of these changes may help to identify therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Updates in the management of polycythemia vera and essential thrombocythemia

2019 ◽  
Vol 10 ◽  
pp. 204062071987005 ◽  
Author(s):  
Prithviraj Bose ◽  
Srdan Verstovsek
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Unmet Need ◽  
Gene Mutations ◽  
Jak2 V617f ◽  
Additional Contribution ◽  
Thrombotic Risk ◽  
Targeted Next Generation Sequencing

Polycythemia vera (PV) and essential thrombocythemia (ET) are both classic, relatively indolent, chronic Philadelphia-chromosome-negative (Ph−) myeloproliferative neoplasms (MPNs) characterized by elevated blood counts, thrombotic as well as hemorrhagic tendencies, a variety of symptoms, cumulative risks of progression to myelofibrosis and transformation to acute myeloid leukemia over time, and long survival. Molecularly, PV is more homogenous, being driven by JAK2 mutations in virtually all cases, while ET can be JAK2-, CALR-, or MPL-mutated, as well as ‘triple negative’. Recent targeted next-generation sequencing efforts have identified other, nondriver gene mutations, some with prognostic relevance. Prevention of thrombotic and hemorrhagic complications continues to be the major focus of management, although symptoms are increasingly being recognized as a relatively unmet need, particularly in ET. Thrombotic risk stratification in PV is still based on age and history of thrombosis, while in ET, the additional contribution of JAK2 V617F to thrombotic risk is now well established. The associations of leukocytosis with clotting risk (in both conditions) and mortality (in PV) have drawn increased attention with the availability of ruxolitinib as a second-line treatment in PV. Similarly, there is a renewed interest in interferons with the emergence of ropeginterferon alfa-2b as a potential new frontline treatment option in PV. Drug development is more difficult in ET, the most indolent of the classic Ph− MPNs, but ruxolitinib is being studied. Triggering apoptosis via the p53 pathway through pharmacologic inhibition of human double minute 2 (and synergism with interferon) is a new, promising therapeutic strategy.

scholarly journals MOLECULAR GENETIC ABNORMALITIES IN THE GENOME OF PATIENTS WITH Ph-NEGATIVE MYELOPROLIFERATIVE NEOPLASIA AFFECTED BY IONIZING RADIATION AS A RESULT OF THE CHORNOBYL NUCLEAR ACCIDENT

2020 ◽  
Vol 25 ◽  
pp. 362-373
Author(s):  
L. Poluben ◽  
◽  
L. Neumerzhytska ◽  
S. Klymenko ◽  
P. Fraenkel ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Radiation Exposure ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Molecular Genetic ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Genomic Research ◽  
History Of

Objective. to determine the frequency of major somatic mutations in the JAK2, MPL and CALR genes in the genome of patients with Ph-negative myeloproliferative neoplasms that occur in individuals who have been exposed to ionizing radiation as a result of the Chornobyl accident. Materials and methods. Molecular genetic analysis of genomic DNA samples isolated from blood was performed in 90 patients with Ph-negative myeloproliferative neoplasia (MPN) with a history of radiation exposure and 191 patients with spontaneous MPN utilizing allele-specific polymerase chain reaction (PCR). Results. The presence of major mutations in the genes JAK2, CALR and MPL was revealed in patients with MPN with a history of radiation exposure with a frequency 58.9 % (53 of 90), 12.2 % (11 of 90), and 0 % respectively, and without exposure with frequency 75.4 % (144 of 191), 3.1 % (6 out of 191) and 1.6 % (3 out of 191) respectively. Mutations JAK2 V617F in patients with spontaneous MPN were observed in each clinical form: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). CALR mutations were detected exclusively in patients with PMF and ET, significantly more often in groups with a radiation exposure history (18.9 % and 33.3 %, vs. 4.2 % and 6.5 %) than without one. At the same time, the occurence of MPL mutations was determined only in patients with spontaneous MPN in 1.6 % of casees. Triple negative mutation status of genes JAK2, MPL and CALR prevailed in the group of patients with MPN with a history of radiation exposure and was 27.8 %, against 16.2 % in patients without radiation exposure (p = 0.05). Conclusions. Genomic research of patients with Ph-negative MPN revealed features of molecular genetic damage in those patients who were exposed to IR as a result of the Chornobyl accident and those with spontaneous MPN. The data obtained by determining of JAK2, MPL and CALR genes mutational status in the genome of patients with MPN is necessary to expand the understanding of the mechanism of leukogenesis, especially caused by radiation. Key words: myeloproliferative neoplasia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, JAK2 V617F, MPL and CALR, ionizing radiation.

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