Myeloproliferative neoplasms (MPNs) are a group of rare chronic progressive blood cancers that vary widely in clinical presentation, yet all patients have a risk of disease progression and thrombotic complications. Diseases include primary myelofibrosis, polycythemia vera, and essential thrombocythemia. With current treatment approaches, most patients live a prolonged life, but many experience a complex of symptoms that negatively influence their functional status and quality of life. Although significant advances have been made in preventing arterial and venous complications while mitigating inflammatory processes, comprehensive palliative care can help address unmet complex physical and psychosocial needs on a long-term basis. This article, created by a multidisciplinary group of providers, offers an overview of MPNs so palliative care clinicians can better support patients with these hematologic cancers.

BACKGROUND: Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia.
METHODS: The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 109/L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 109/L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 109/L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes.
CONCLUSIONS: To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia.

C-Mannosyl tryptophan (CMW), a unique glycosylated amino acid, is considered to be produced by degradation of C-mannosylated proteins in living organism. Although protein C-mannosylation is involved in the folding and secretion of substrate proteins, the pathophysiological function in the hematological system is still unclear. This study aimed to assess CMW in the human hematological disorders. The serum CMW levels of 94 healthy Japanese workers were quantified using hydrophilic interaction liquid chromatography. Platelet count was positively correlated with serum CMW levels. The clinical significance of CMW in thrombocytosis of myeloproliferative neoplasms (T-MPN) including essential thrombocythemia (ET) were investigated. The serum CMW levels of the 34 patients with T-MPN who presented with thrombocytosis were significantly higher than those of the 52 patients with control who had other hematological disorders. In patients with T-MPN, serum CMW levels were inversely correlated with anemia, which was related to myelofibrosis (MF). Bone marrow biopsy samples were obtained from 18 patients with ET, and serum CMW levels were simultaneously measured. Twelve patients with bone marrow fibrosis had significantly higher CMW levels than 6 patients without bone marrow fibrosis. Collectively, these results suggested that CMW could be a novel biomarker to predict MF progression in T-MPN.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by persistent elevation of platelet count due to abnormal proliferation of megakaryocytes. While some cases may be asymptomatic, the condition is associated with an increased risk of complications such as thrombosis and bleeding tendencies, necessitating appropriate management tailored to individual cases. Hemostasis analyzer systems are automated analytical devices designed for comprehensive evaluation of blood coagulation function. These systems enable rapid and accurate measurement of multiple parameters, including coagulation time, platelet function, and fibrin formation, thus facilitating a holistic assessment of hemostatic function. A 76-year-old male patient presented to our hospital. At the age of 65, he received treatment for promyelocytic leukemia and achieved remission. At 75 years, he developed leukocytosis, thrombocytosis, and progressive anemia. A comprehensive examination, including bone marrow biopsy and genetic testing, revealed a JAK2 mutation, leading to the diagnosis of ET. At the age of 76 years, he complained of chest discomfort during exertion. Further investigation revealed severe aortic valve stenosis and two-vessel coronary artery disease. The patient underwent aortic valve replacement and three-vessel coronary artery bypass grafting. A hemostasis analyzer system was used to monitor coagulation function throughout the procedure. Compared with the normal range, his coagulation profile showed a tendency toward hypercoagulability. Intraoperative and postoperative transfusions were performed as required. The patient\'s postoperative course was uneventful without any complications related to bleeding or thrombosis.

Calreticulin (CRT) is an intrinsically disordered multifunctional protein that plays essential roles intra-and extra-cellularly. The Michalak laboratory has proposed that CRT was initially identified in 1974 by the MacLennan laboratory as the high-affinity Ca2+-binding protein (HACBP) of the sarcoplasmic reticulin (SR). This widely accepted belief has been ingrained in the scientific literature but has never been rigorously tested. In our report, we have undertaken a comprehensive reexamination of this assumption by meticulously examining the majority of published studies that present a proteomic analysis of the SR. These analyses have utilized proteomic analysis of purified SR preparations or purified components of the SR, namely the longitudinal tubules and junctional terminal cisternae. These studies have consistently failed to detect the HACBP or CRT in skeletal muscle SR. We propose that the existence of the HACBP has failed the test of reproducibility and should be retired to the annals of antiquity. Therefore, the scientific dogma that the HACBP and CRT are identical proteins is a non sequitur.

BACKGROUND: Essential thrombocythemia (ET) involves the proliferation of megakaryocytes and platelets and is associated with an increased risk of thrombosis. We aimed to evaluate thrombotic risks in patients with epigenetic regulator mutations and generate a model to predict thrombosis in ET.
METHODS: This cohort study enrolled patients aged > 15 years diagnosed with ET at the Songklanakarind Hospital between January 2002 and December 2019. Twenty-five targeted gene mutations, including somatic driver mutations (JAK2, CALR, MPL), epigenetic regulator mutations (TET2, DNMT3A, IDH1, IDH2, TET2, ASXL1, EZH2, SF3B1, SRSF2) and other genes relevant to myeloid neoplasms, were identified using next-generation sequencing. Thrombotic events were confirmed based on clinical condition and imaging findings, and thrombotic risks were analyzed using five survival models with the recurrent event method.
RESULTS: Ninety-six patients were enrolled with a median follow-up of 6.91 years. Of these, 15 patients experienced 17 arterial thrombotic events in total. Patients with JAK2 mutation and IDH1 mutation had the highest frequency of thrombotic events with somatic driver mutations (17.3%) and epigenetic regulator mutations (100%). The 10-year thrombosis-free survival rate was 81.3% (95% confidence interval: 72.0-91.8%). IDH1 mutation was a significant factor for thrombotic risk in the multivariate analysis for all models. The Prentice, William, and Peterson (PWP) gap-time model was the most appropriate prediction model.
CONCLUSIONS: The PWP gap-time model was a good predictive model for thrombotic risk in patients with ET. IDH1 mutation was significant risk factors for thrombosis; however, further studies with a larger sample size should confirm this and provide more insight.

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre-PMF) are Philadelphia chromosome-negative myeloproliferative neoplasms. These conditions share overlapping clinical presentations; however, their prognoses differ significantly. Current morphological diagnostic methods lack reliability in subtype differentiation, underlining the need for improved diagnostics. The aim of this study was to investigate the multi-omics alterations in bone marrow biopsies of patients with ET and pre-PMF to improve our understanding of the nuanced diagnostic characteristics of both diseases. We performed proteomic analysis with 4D direct data-independent acquisition and microbiome analysis with 2bRAD-M sequencing technology to identify differential protein and microbe levels between untreated patients with ET and pre-PMF. Laboratory and multi-omics differences were observed between ET and pre-PMF, encompassing diverse pathways, such as lipid metabolism and immune response. The pre-PMF group showed an increased neutrophil-to-lymphocyte ratio and decreased high-density lipoprotein and cholesterol levels. Protein analysis revealed significantly higher CXCR2, CXCR4, and MX1 levels in pre-PMF, while APOC3, APOA4, FABP4, C5, and CFB levels were elevated in ET, with diagnostic accuracy indicated by AUC values ranging from 0.786 to 0.881. Microbiome assessment identified increased levels of Mycobacterium, Xanthobacter, and L1I39 in pre-PMF, whereas Sphingomonas, Brevibacillus, and Pseudomonas_E were significantly decreased, with AUCs for these genera ranging from 0.833 to 0.929. Our study provides preliminary insights into the proteomic and microbiome variations in the bone marrow of patients with ET and pre-PMF, identifying specific proteins and bacterial genera that warrant further investigation as potential diagnostic indicators. These observations contribute to our evolving understanding of the multi-omics variations and possible mechanisms underlying ET and pre-PMF.

We previously reported the Marimo cell line, which was established from the bone marrow cells of a patient with essential thrombocythemia (ET) at the last stage after transformation to acute myeloid leukemia (AML). This cell line is widely used for the biological analysis of ET because it harbors CALR mutation. However, genetic processes during disease progression in the original patient were not analyzed. We sequentially analyzed the genetic status in the original patient samples during disease progression. The ET clone had already acquired CALR and MPL mutations, and TP53 and NRAS mutations affected the disease progression from ET to AML in this patient. Particularly, the variant allele frequency of the NRAS mutation increased along with the disease progression after transformation, and the NRAS-mutated clone selectively proliferated in vitro, resulting in the establishment of the Marimo cell line. Although CALR and MPL mutations co-existed, MPL was not expressed in Marimo cells or any clinical samples. Furthermore, mitogen-activated protein kinase (MAPK) but not the JAK2-STAT pathway was activated. These results collectively indicate that MAPK activation is mainly associated with the proliferation ability of Marimo cells.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark CALR mutation transforming to AML characterized by a previously unreported AKAP9::PDGFRA fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.

Myeloproliferative neoplasms (MPNs) occur due to the abnormal proliferation of one or more terminal myeloid cell lines in peripheral blood. Subjects suffering from MPNs display a high burden of cardiovascular risk factors, and thrombotic events are often the cause of death in this population of patients. Herein, we provide a brief overview of dyslipidemia and metabolic syndrome and their epidemiology in MPNs and examine the common molecular mechanisms between dyslipidemia, metabolic syndrome, and MPNs, with a special focus on cardiovascular risk, atherosclerosis, and thrombotic events. Furthermore, we investigate the impact of dyslipidemia and metabolic syndrome on the occurrence and survival of thrombosis in MPN patients, as well as the management of dyslipidemia in MPNs, and the impact of MPN treatment on serum lipid concentrations, particularly as side/adverse effects reported in the context of clinical trials.