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ObjectiveTo further understand the factors that promote thrombosis in essential thrombocythemia （ET） that were not included in IPSET-thrombosis （International Prognostic Score of Thrombosis for ET）. MethodsA systematic evaluation was conducted on 292 studies by retrieving PubMed，Web of Science, and The Cochrane Library. The incidence and relative risk ratio （RR） of thrombosis in ET patients with different risk factors were calculated. The confidence levels for the outcome were analyzed in combination with RR values and recommendation scores (RS) to find the thrombotic risk factors in ET patients. ResultsOut of 9 risk factors that promoted ET thrombosis, there were 4 factors in IPSET-thrombosis, including history of thrombosis （35.0%, RR=3.30, 95% CI : 2.30-4.75）, JAK2V617F positive （21.0%, RR=2.28, 95%CI : 1.14-4.56）, age over 60 years old （ 22.4% , RR=1.95, 95%CI : 1.17-3.23） and cardiovascular risk factors （17.7%, RR =1.90, 95%CI : 1.08-3.35）. The remaining five risk factors, not listed in IPSET-thrombosis, included monoclonal type of ET based on X-chromosome inactivation pattern （XCIP, 30.6%, RR=4.49, 95% CI: 1.58-12.77）, high JAK2V617F burden （33.9%, RR=3.69, 95%CI: 1.70-7.99）, leukocytosis （18.7%, RR=3.05, 95%CI: 1.81-5.13）, MPL mutation （22.1%, RR=2.40, 95%CI: 1.08-5.33） and splenomegaly （25.6%, RR=1.76, 95%CI：1.29-2.40）. ConclusionAmong the risk factors promoting thrombosis in ET patients, five thrombotic risk factors not included in the IPSET-thrombosis have been identified.

Since MPL mutation is a rare driver gene mutation found in a small number of essential thrombocythemia (ET) patients, the clinical characteristics of patients with MPL mutations and their association with thrombotic events have not yet been elucidated in Japan. We enrolled 579 Japanese ET patients based on the diagnostic criteria of the WHO classification 2017 and compared clinical characteristics of MPL-mutated patients (n = 22; 3.8%) to JAK2V617F-mutated (n = 299; 51.6%), CALR-mutated (n = 144; 24.9%), and triple-negative (TN) (n = 114; 19.7%) patients. Thrombosis during follow up was observed in 4 out of 22 (18.2%) in the MPL-mutated group, which was the highest among all driver gene mutation groups (JAK2V617F-mutated, 8.7%; CALR-mutated, 3.5%; TN,1.8%). The MPL- and JAK2V617F-mutated groups had worse thrombosis-free survival (TFS) than the CALR-mutated (p = 0.043) and TN groups (p = 0.006). Univariable analysis revealed that a history of thrombosis was a possible risk factor for thrombosis among MPL-mutated patients (hazard ratio: 9.572, p = 0.032). MPL-mutated ET patients should require more intensive management to prevent recurrence of thrombosis. [ABSTRACT FROM AUTHOR]

ABSTRACTObjectives Since MPL mutation is a rare driver gene mutation found in a small number of essential thrombocythemia (ET) patients, the clinical characteristics of patients with MPL mutations and their association with thrombotic events have not yet been elucidated in Japan.Methods We enrolled 579 Japanese ET patients based on the diagnostic criteria of the WHO classification 2017 and compared clinical characteristics of MPL-mutated patients (n = 22; 3.8%) to JAK2V617F-mutated (n = 299; 51.6%), CALR-mutated (n = 144; 24.9%), and triple-negative (TN) (n = 114; 19.7%) patients.Results Thrombosis during follow up was observed in 4 out of 22 (18.2%) in the MPL-mutated group, which was the highest among all driver gene mutation groups (JAK2V617F-mutated, 8.7%; CALR-mutated, 3.5%; TN,1.8%). The MPL- and JAK2V617F-mutated groups had worse thrombosis-free survival (TFS) than the CALR-mutated (p = 0.043) and TN groups (p = 0.006). Univariable analysis revealed that a history of thrombosis was a possible risk factor for thrombosis among MPL-mutated patients (hazard ratio: 9.572, p = 0.032).Conclusions MPL-mutated ET patients should require more intensive management to prevent recurrence of thrombosis.

Objectives The current study aimed to explore the incidence of MPL mutations and the clinical and molecular characteristics of AML with MPL mutation.Methods In total, 1509 patients with newly diagnosed AML were retrospectively analyzed between January 2017 and December 2020. MPL mutations were detected via next-generation sequencing. During the same period, we also enrolled 30 patients with other myeloid neoplasms (MNs) with MPL mutation, which included myelodysplastic syndrome (n = 15), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) (n = 6), and MPN (n = 9). The clinical characteristics of MPL-mutated AML and other types of MNs or MPL-wide type (MPL-wt) AML were compared, and the spectrum of co-mutations and MPL mutation profiles in MPL-mutated AML were analyzed.Results MPL mutations were identified in 19 (1.26%) of 1509 patients with AML. The waterfall diagram showed that the co-mutations were mainly epigenetic modifications (TET2, IDH1, and EZH2), spliceosomes (SRSF2), and transcription factors (RUNX1). The platelet count of the AML group was significantly lower than that of the MPN group (p = 0.001). MPL mutations were commonly observed in the intracellular region in AML but the transmembrane region in MPN (p = 0.013). The MPL-mutated AML group had a lower white blood cell count and a lower rate of complete remission than the MPL wild-type AML group (p = 0.037).Conclusion MPL mutations are clinically relevant in patients with AML, and they may be a novel subtype characterized by lower white blood cell counts and poor complete remission rates. However, further studies must be conducted to identify its correlated mechanism.

Acute lymphoblastic leukemia (ALL) arising in preexisting myeloproliferative neoplasms (MPN) is rare with historical cases unable to differentiate between concomitant malignancies or leukemic transformation. Here, we report a case of patient with Philadelphia positive B lymphoblastic leukemia (Ph+ALL) who developed from MPL-mutated essential thrombocythemia (ET) 13 years after initial presentation. Molecular studies showed the discrepancy between the high percentage of lymphocyte blasts (91%) and the low MPL p.(W515L) variant allele frequency (2.59%) at diagnosis in the bone marrow, indicating that the Ph+ALL clone did not originate from the ET clone carrying the MPL p.(W515L) variant. After the treatment of a new tyrosine kinase inhibitor flumatinib and prednisolone, cytogenetic and molecular remission had been achieved rapidly and followed by the recovery of original ET manifestation. Although relapsed eventually, this is still a very rare case of simultaneous presence of two cytogenetics abnormalities and evolution of MPL p.(W515L) variant ET to Ph+ALL and may provide evidence to illustrate the clonal relationship of MPN and post-MPN ALL.

The current study aimed to explore the incidence of MPL mutations and the clinical and molecular characteristics of AML with MPL mutation. In total, 1509 patients with newly diagnosed AML were retrospectively analyzed between January 2017 and December 2020. MPL mutations were detected via next-generation sequencing. During the same period, we also enrolled 30 patients with other myeloid neoplasms (MNs) with MPL mutation, which included myelodysplastic syndrome (n = 15), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) (n = 6), and MPN (n = 9). The clinical characteristics of MPL-mutated AML and other types of MNs or MPL-wide type (MPL-wt) AML were compared, and the spectrum of co-mutations and MPL mutation profiles in MPL-mutated AML were analyzed. MPL mutations were identified in 19 (1.26%) of 1509 patients with AML. The waterfall diagram showed that the co-mutations were mainly epigenetic modifications (TET2, IDH1, and EZH2), spliceosomes (SRSF2), and transcription factors (RUNX1). The platelet count of the AML group was significantly lower than that of the MPN group (p = 0.001). MPL mutations were commonly observed in the intracellular region in AML but the transmembrane region in MPN (p = 0.013). The MPL-mutated AML group had a lower white blood cell count and a lower rate of complete remission than the MPL wild-type AML group (p = 0.037). MPL mutations are clinically relevant in patients with AML, and they may be a novel subtype characterized by lower white blood cell counts and poor complete remission rates. However, further studies must be conducted to identify its correlated mechanism. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) arising in preexisting myeloproliferative neoplasms (MPN) is rare with historical cases unable to differentiate between concomitant malignancies or leukemic transformation. Here, we report a case of patient with Philadelphia positive B lymphoblastic leukemia (Ph+ALL) who developed from MPL-mutated essential thrombocythemia (ET) 13 years after initial presentation. Molecular studies showed the discrepancy between the high percentage of lymphocyte blasts (91%) and the low MPL p.(W515L) variant allele frequency (2.59%) at diagnosis in the bone marrow, indicating that the Ph+ALL clone did not originate from the ET clone carrying the MPL p.(W515L) variant. After the treatment of a new tyrosine kinase inhibitor flumatinib and prednisolone, cytogenetic and molecular remission had been achieved rapidly and followed by the recovery of original ET manifestation. Although relapsed eventually, this is still a very rare case of simultaneous presence of two cytogenetics abnormalities and evolution of MPL p.(W515L) variant ET to Ph+ALL and may provide evidence to illustrate the clonal relationship of MPN and post-MPN ALL. [ABSTRACT FROM AUTHOR]

Summary: Familial thrombocytosis (FT) is a rare hereditary haematological disorder characterised by increased platelet count, usually caused by germ‐line mutations in thrombopoietin (THPO), myeloproliferative leukaemia virus oncogene (MPL) or Janus kinase 2 (JAK2) genes, and can be associated with increased risk of thrombosis. We aimed to determine the yield of diagnostic tests, assess treatment received and describe the clinical course of MPL‐associated FT. We retrospectively reviewed all paediatric and adult haematology patients diagnosed with MPL‐related FT, who were seen in our clinics from March 2013 to February 2021. Of 64 eligible patients, 26 (41%) were aged <14 years, while the remaining 38 (59%) patients were adults. The median (interquartile range) age at diagnosis was 20 (33·5) years. In all, 26 tribes were represented in this cohort of 64 patients, out of which 31 (48%) patients belonged to two tribes. A total of 60 patients (94%) had thrombocytosis on blood count. Additional genetic tests, including myelodysplastic syndrome (MDS) gene panel, Philadelphia gene breakpoint cluster region‐Abelson (BCR‐ABL) and JAK2, were carried out for 52 patients and only one patient was positive for JAK2 mutation. In all, 21 (33%) patients were prescribed aspirin and seven (11%) were prescribed hydroxyurea. Overall, 63 (98%) patients did not develop any thrombotic or haemorrhagic event. There was no significant association of MPL‐mutated FT with thrombosis or haemorrhage. [ABSTRACT FROM AUTHOR]

Abstract MPLW515K or W515L mutation plays an important role in the pathogenesis of myeloproliferative neoplasms (MPNs) through signaling molecules of the cytokine receptor axis. Besides MPLW515K or W515L, more than 30 atypical MPL mutations have been reported in patients who are negative for JAK2V617F, MPLW515K/L, and CALR mutations. Here, we aimed to identify the disease‐causing mutations in the triple‐negative case of ET. We described two MPL mutations in patients diagnosed with ET by target sequencing the hotspot mutation region of MPL gene. The MPLA497‐L498ins4 is an insertion mutation detected recurrently in ET patients, and the MPLW515RQ516E is a novel double‐point mutation found in an ET patient. Functional studies of MPLA497‐L498ins4 and MPLW515RQ516E revealed that they are gain‐of‐function mutations. Mutants of MPLA497‐L498ins4 and MPLW515RQ516E promoted autonomous proliferation on Ba/F3 cells in the absence of IL‐3. Autonomous activation of TPO‐R without ligand TPO was observed in MPLA497‐L498ins4 and MPLW515RQ516E mutants. Lower percentage of cells in G1 phase and higher percentage of cells in S phase of two atypical MPL mutants were detected after culturing without any cytokines. These two atypical MPL mutations also presented increase in phosphorylation of signaling proteins including JAK2/STAT, PI3K/AKT, and MAPK/RAS. In summary, the MPLA497‐L498ins4 and MPLW515RQ516E are gain‐of‐function mutations which may be novel driving factors participating in the pathogenesis of triple‐negative MPN.

MPLW515K or W515L mutation plays an important role in the pathogenesis of myeloproliferative neoplasms (MPNs) through signaling molecules of the cytokine receptor axis. Besides MPLW515K or W515L, more than 30 atypical MPL mutations have been reported in patients who are negative for JAK2V617F, MPLW515K/L, and CALR mutations. Here, we aimed to identify the disease‐causing mutations in the triple‐negative case of ET. We described two MPL mutations in patients diagnosed with ET by target sequencing the hotspot mutation region of MPL gene. The MPLA497‐L498ins4 is an insertion mutation detected recurrently in ET patients, and the MPLW515RQ516E is a novel double‐point mutation found in an ET patient. Functional studies of MPLA497‐L498ins4 and MPLW515RQ516E revealed that they are gain‐of‐function mutations. Mutants of MPLA497‐L498ins4 and MPLW515RQ516E promoted autonomous proliferation on Ba/F3 cells in the absence of IL‐3. Autonomous activation of TPO‐R without ligand TPO was observed in MPLA497‐L498ins4 and MPLW515RQ516E mutants. Lower percentage of cells in G1 phase and higher percentage of cells in S phase of two atypical MPL mutants were detected after culturing without any cytokines. These two atypical MPL mutations also presented increase in phosphorylation of signaling proteins including JAK2/STAT, PI3K/AKT, and MAPK/RAS. In summary, the MPLA497‐L498ins4 and MPLW515RQ516E are gain‐of‐function mutations which may be novel driving factors participating in the pathogenesis of triple‐negative MPN. [ABSTRACT FROM AUTHOR]

Introduction: Mutations in the JAK2, CALR, and MPL genes have been shown to have prognostic value in essential thrombocythaemia (ET), but no clear association with morphological changes has been reported so far. We investigated the possible correlation between gene mutations and histopathological features in bone marrow (BM) biopsies of patients with ET. Methods: Marrow cellularity, fibrosis, and the number of total and dysmorphic megakaryocytes and clusters of megakaryocytes were compared to gene mutations in 90 cases of ET at diagnosis. Results: The JAK2V617F mutation was found in 58.9%, CALR in 28.9%, and MPL in 4.4% of the cases, and 7.8% were triple-negative. JAK2V617F-mutated ET showed a high BM cellularity, the lowest number of clusters of megakaryocytes and the highest number of dysmorphic megakaryocytes; CALR-mutated ET showed a reduced BM cellularity, many clusters of large megakaryocytes, and very few dysmorphic megakaryocytes; MPL-mutated ET showed the lowest BM cellularity, the highest number of clustered and large megakaryocytes, and the lowest number of dysmorphic megakaryocytes. Triple-negative ET cases had the highest BM cellularity. Conclusions: Distinct morphological patterns were associated with gene mutations in ET, supporting the classification of ET into different subtypes. [ABSTRACT FROM AUTHOR]

Background and Aims Myeloproliferative neoplasms (MPN) are the leading cause of splanchnic vein thrombosis (SVT). Janus kinase 2 gene ( JAK2 ) V617F mutations are found in 80 to 90% of patients with SVT and MPN. Mutations of the calreticulin ( CALR ) gene have also been reported. However, as their prevalence ranges from 0 to 2%, the utility of routine testing is questionable. This study aimed to identify a group of patients with SVT at high risk of harboring CALR mutations and thus requiring this genetic testing. Methods CALR , JAK2 V617F and thrombopoietin receptor gene ( MPL ) mutations were analysed in a test cohort that included 312 patients with SVT. Criteria to identify patients at high risk of CALR mutations in this test cohort was used and evaluated in a validation cohort that included 209 patients with SVT. Results In the test cohort, 59 patients had JAK2 V617F , five had CALR and none had MPL mutations. Patients with CALR mutations had higher spleen height and platelet count than patients without these mutations. All patients with CALR mutations had a spleen height ⩾16 cm and platelet count >200×10 9 /L. These criteria had a positive predictive value of 56% (5/9) and a negative predictive value of 100% (0/233) for the identification of CALR mutations. In the validation cohort, these criteria had a positive predictive value of 33% (2/6) and a negative predictive value of 99% (1/96). Conclusion CALR mutations should be tested in patients with SVT, a spleen height ⩾16 cm, platelet count >200×10 9 /L, and no JAK2 V617F . This strategy avoids 96% of unnecessary CALR mutations testing. Lay summary: Mutations of the CALR gene are detected in 0 to 2% of patients with SVT, thus the utility of systematic CALR mutation testing to diagnose MPN is questionable. This study demonstrates that CALR mutations testing can be restricted to patients with SVT, a spleen height ⩾16 cm, a platelet count >200×10 9 /L, and no JAK2 V617F . This strategy avoids 96% of unnecessary CALR mutations testing. [ABSTRACT FROM AUTHOR]

The risk of complication of polycythemia vera (PV) and essential thrombocythemia (ET) by thrombosis in Japanese patients is clearly lower than in western populations, suggesting that genetic background such as race may influence the clinical features. This study aimed to clarify the relationship between genetic mutations and haplotypes and clinical features in Japanese patients with PV and ET. Clinical features were assessed prospectively among 74 PV and 303 ET patients. There were no clinical differences, including JAK2V617F allele burden, between PV patients harboring the various genetic mutations. However, CALR mutation-positive ET patients had a significantly lower WBC count, Hb value, Ht value, and neutrophil alkaline phosphatase score (NAP), and significantly more platelets, relative to JAK2V617F -positive ET patients and ET patients with no mutations. Compared to normal controls, the frequency of the JAK2 46/1 haplotype was significantly higher among patients with JAK2V617F , JAK2Ex12del , or MPL mutations, whereas no significant difference was found among CALR mutation-positive patients. CALR mutation-positive patients had a lower incidence of thrombosis relative to JAK2V617F- positive patients. Our findings suggest that JAK2V617F -positive ET patients and CALR mutation-positive patients have different mechanisms of occurrence and clinical features of ET, suggesting the potential need for therapy stratification in the future. [ABSTRACT FROM AUTHOR]

Keywords: essential thrombocythaemia; familial thrombocythaemia; MPL mutation EN essential thrombocythaemia familial thrombocythaemia MPL mutation 808 809 2 09/02/21 20210901 NES 210901 Familial thrombocythaemia (FT) includes a group of predominantly autosomal dominant conditions due to various mutations in the thrombopoietin ( I THPO i ), myeloproliferative leukaemia virus oncogene ( I MPL) i , or Janus kinase 2 ( I JAK2 i ) genes.1 These disorders differ from essential thrombocythaemia (ET), one of the classical, Philadelphia chromosome breakpoint cluster region-Abelson tyrosine-protein kinase 1 ( I BCR-ABL1 i )-negative myeloproliferative neoplasms (which are a group of diseases characterised by vascular and bleeding complications and risk of fibrotic or leukaemic transformation.) Clinical course of myeloproliferative leukaemia virus oncogene (MPL) mutation-associated familial thrombocytosis: a review of 64 paediatric and adult patients [Online ahead of print]. Clinical course of myeloproliferative leukaemia virus oncogene ( I MPL i ) mutation-associated familial thrombocytosis: a review of 64 paediatric and adult patients. [Extracted from the article]

Calreticulin ( CALR) mutations were recently identified in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) devoid of JAK2 and MPL mutations. We evaluated the clinical, laboratory, and molecular features of a Taiwanese population of patients with ET. Among 147 ET patients, CALR mutations were detected in 33 (22.5 %), JAK2V617F in 94 (63.9 %), and MPL mutations in 4 (2.7 %). Sixteen (10.9 %) patients were negative for all three mutations ( CALR, JAK2V617F, and MPL; triple negative). Interestingly, one patient with the type 2 CALR mutation also harbored a low allele burden (0.025 %) of JAK2V617F mutation. Furthermore, we found a novel CALR mutation, with the resultant protein sharing an identical amino acid sequence to the type 6 CALR mutant. Compared to those with JAK2 mutation, CALR-mutated ET patients were characterized by younger age, lower leukocyte count, higher platelet count, and decreased risk of thrombosis. CARL mutations had a favorable impact on thrombosis-free survival (TFS) for ET patients, whereas the respective TFS outcomes were similarly poorer in JAK2-mutated ET and PV patients. Multivariate analysis confirmed that younger age (<60 years), presence of CALR mutations, and a lower platelet count (<1,000 × 10/L) were independently associated with a longer TFS in ET patients. The current study demonstrates that CALR mutations characterize a special group of ET patients with unique phenotypes that are not discrepant from those seen in Western countries. [ABSTRACT FROM AUTHOR]

B-lymphoblastic leukemia (B-ALL) is a neoplasm of precursors committed to B-cell lineage, whereas myeloproliferative neoplasm (MPN) is a clonal proliferation derived from myeloid stem cells. Concurrent B-ALL with MPN is uncommon except in the presence of abnormalities of the PDGFRA, PDGFRB, or FGFR1 genes or the BCR-ABL1 fusion gene. Herein, we describe a rare concurrence, B-ALL with MPN without the aforementioned genetic aberrations, in a 64-year-old male patient. The patient was initially diagnosed with B-ALL with normal karyotype and responded well to aggressive chemotherapy but had sustained leukocytosis and splenomegaly. The posttreatment restaging bone marrow was free of B-ALL but remained hypercellular with myeloid predominance. Using a single nucleotide polymorphism microarray study, we identified a copy neutral loss of heterozygosity at the terminus of 1p in the bone marrow samples taken at diagnosis and again at remission, 49% and 100%, respectively. Several additional genetic abnormalities were present in the initial marrow sample but not in the remission marrow samples. Retrospective molecular studies detected a MPL W515S homozygous mutation in both the initial and remission marrows for B-ALL, at 30–40% and 80% dosage effect, respectively. In summary, we present a case of concurrent B-ALL and MPN and demonstrate a stepwise cytogenetic and molecular approach to the final diagnosis. [ABSTRACT FROM AUTHOR]

• The myeloproliferative neoplasms • The molecular pathogenesls of MPN • Epigenetic events In cancer • Epigenetic events In MPN • Drugs for epigenetic therapy • Epigenetic therapy In MPN • Conclusions The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), which include polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, originate from a stem cell-derived clonal myeloproliferation that manifests itself with variable haematopoietic cell lineage involvement; they are characterized by a high degree of similarities and the chance to transform each to the other and to evolve into acute leukaemia. Their molecular pathogenesis has been associated with recurrent acquired mutations in janus kinase 2 (JAK2) and myeloproliferative leukemia virus oncogene (MPL). These discoveries have simplified the diagnostic approach and provided a number of clues to understanding the phenotypic expression of MPNs; furthermore, they represented a framework for developing and/or testing in clinical trials small molecules acting as tyrosine kinase inhibitors. On the other hand, evidence of abnormal epigenetic gene regulation as a mechanism potentially contributing to the pathogenesis and the phenotypic diversity of MPNs is still scanty; however, study of epigenetics in MPNs represents an active field of research. The first clinical trials with epigenetic drugs have been completed recently, whereas others are still ongoing; results have been variable and at present do not allow any firm conclusion. Novel basic and translational information concerning epigenetic gene regulation in MPNs and the perspectives for therapy will be critically addressed in this review. [ABSTRACT FROM AUTHOR]

The Philadelphia chromosome-negative myeloproliferative disorders (MPDs) polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF) are characterized by increased proliferation of terminally differentiated myeloid cells. Although these disorders were recognized as clonal hematopoietic stem cell disorders more than 3 decades ago, little was known about the genetic basis for these disorders until 2005 when a single recurrent mutation in the JAK2 tyrosine kinase (JAK2V617F) was identified in >90% of patients with PV and in a significant proportion of patients with ET and PMF. JAK2V617F is a constitutively active tyrosine kinase and has transforming properties in vitro and in vivo, providing validation JAK2V617F is a bona fide oncogene which contributes to MPD pathogenesis. Subsequent studies of JAK2V617F-negative MPDs have identified mutations in JAK2 exon 12 and MPL, and these mutations also result in constitutive activation of JAK2 signaling. In this review, we will discuss the genetics of PV, ET and PMF with regard to known somatic mutations, the role of these mutations in hematopoietic transformation and the therapeutic implications of these findings. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The clinical and haematological phenotype of patients with myelofibrosis harbouring MPL W515 L/ K mutation has not been thoroughly investigated. Of 217 myelofibrosis subjects, 18 (8·2%) had an MPL mutation, four of which (22%) co-existed with JAK2 V617 F mutation. When compared with MPL wild-type patients, irrespective of JAK2 V617 F status, those with MPL W515 L/ K, were more frequently female, were older (61 years vs. 57 years; P = 0·02), presented with more severe anaemia (haemoglobin, 101 g/l vs. 121 g/l; P = 0·002) and were more likely to require regular transfusional support ( P = 0·012). These data indicate that MPL mutation in myelofibrosis characterises patients with more severe anaemic phenotype. [ABSTRACT FROM AUTHOR]

Essential thrombocythemia (ET) is a subtype of myeloproliferative neoplasms. Approximately half of the patients with ET harbor a gain-of-function mutation in the JAK2 gene ( JAK2-V617F), a small percentage have mutations in codon 515 of MPL (thrombopoietin receptor) gene, and the rest have neither mutation. Pregnancy is a rare complication of ET, and it has been reported that the number of blood platelets falls with pregnancy in ET patients and the number of blood platelets increases again after a delivery and this phenomenon is observed in JAK2-V617F-positive and JAK2-V617F-negative patients. We report the first case of an ET patient with MPL mutations, whose platelet count improved with the onset of menopause, not pregnancy, and the MPL mutation also simultaneously disappeared. [ABSTRACT FROM AUTHOR]

Background: The discovery of Janus kinase 2 (JAK2)-V617F has provided important insight into the pathogenesis of Philadelphia-negative chronic myeloproliferative neoplasms (Ph-negative MPNs); however, the etiology of JAK2V617F-negative Ph-negative MPN remains unidentified. MPLW515L and MPLW515K (MPLW515L/K) are 2 gain-of-function mutations, which have been found in some Ph-negative MPN patients from Western countries. However, little is known about the incidence of these mutations in Taiwanese Ph-negative MPN patients. Methods: We determined the MPL sequence of DNA samples from 105 patients, including 88 patients with Ph-negative MPNs and 17 with myelodysplastic syndrome, using polymerase chain reaction amplification of the cytokine receptor MPL exon 10 sequence. Results: All the patients were normal at codon 515 regardless of their JAK2 status. Conclusion: The MPL W515L/K mutations are rare in Taiwanese patients with Ph-negative MPNs. [Copyright &y& Elsevier]

Sequential genotyping for phenotype-driver mutations in JAK2 (exon 14), CALR (exon 9), and MPL (exon 10) is recommended in patients with myeloproliferative neoplasms. Yet, atypical JAK2- and MPL-mutations were described in some triple-negative patients. Whether noncanonical and/or concomitant JAK2- and MPL-mutations exist in myelofibrosis (MF) regardless of phenotype-driver mutations is not yet elucidated. For this, next-generation sequencing (NGS) was performed using blood genomic DNA from 128 MF patients (primary MF, n = 93; post-ET-MF, n = 18; post-PV-MF, n = 17). While no atypical JAK2- or MPL-mutations were seen in 24 CALR-positive samples, two JAK2-mutations [c.3323A > G, p.N1108S; c.3188G > A, p.R1063H] were detected in two of the 21 (9.5%) triple-negative patients. Twelve of the 82 (14.6%) JAK2V617F-positive cases had coexisting germline JAK2-mutations [JAK2R1063H, n = 6; JAK2R893T, n = 1; JAK2T525A, n = 1] or at least one somatic MPL-mutation [MPLY591D, n = 3; MPLW515 L, n = 2; MPLE335K, n = 1]. Overall, MPL-mutations always coexisted with JAK2V617F and/or other MPL-mutations. None of the JAK2V617F plus a second JAK2-mutation carried a TET2-mutation but all patients with JAK2V617F plus an MPL-mutation harbored a somatic TET2-mutation. Four genomic clusters could be identified in the JAK2V617F-positive cohort. Cluster-I (10%) (noncanonical JAK2 mutated (mut)  + TET2 wildtype (wt) ) were younger and had less proliferative disease compared with cluster-IV (5%) (TET2 mut  + MPL mut ). In conclusion, recurrent concomitant classical and/or noncanonical JAK2- and MPL-mutations could be detected by NGS in 15.7% of JAK2V617F- and MPLW515-positive MF patients with genotype-phenotype associations. Many of the germline and/or somatic mutations might act as "Significantly Mutated Genes" contributing to the pathogenesis and phenotypic heterogeneity. A cost-effective NGS-based approach might be an important step towards patient-tailored medicine., (© 2019 Wiley Periodicals, Inc.)