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.

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.

Due to the thrombohemorrhagic potential of essential thrombocythemia, pregnancy complicated by essential thrombocythemia should be recognized as a risk factor for obstetric complications. Here, we report the case of a patient with essential thrombocythemia with two significantly different pregnancy outcomes. Her first pregnancy (at 30 years of age) ended with an uneventful term delivery. However, the patient progressed to cavernous transformation of the portal vein in the period between her two pregnancies and subsequently experienced deep venous thrombosis during the first trimester of her second pregnancy (at 36 years of age). The patient\'s platelet count during pregnancy was within the normal range, so she ignored previous instances of essential thrombocytosis (at 26 years of age). The patient\'s main symptom was unrelieved pain in her leg. After that, she was successfully treated with anticoagulant throughout her entire pregnancy, resulting in a term vaginal delivery. This case highlights the importance of assessing pregnant patients with essential thrombocythemia according to their risk stratification. Specifically, risk assessments for potential pregnancy complications should take into account advanced maternal age and a previous history of thrombosis. Patients with essential thrombocythemia should be encouraged to participate in preconception counseling for risk assessment and to initiate prophylactic anticoagulation as soon as possible.

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UNASSIGNED: It has been discovered that Janus kinase 2 (JAK2) exon12 mutations lead to the polycythemia vera (PV) phenotype, while somatic mutations of calreticulin (CALR) are associated with essential thrombocythemia (ET) or primary myelofibrosis. In this article, we report a case of ET with coexistence of JAK2 exon12 and CALR mutations. The objective of this study was to elucidate the pathogenicity mechanism of a JAK2 exon12 mutation (JAK2N533S) and the role of the coexistence of mutations on the hematological phenotype.
UNASSIGNED: We designed a colony analysis of tumor cells obtained from this patient, and attempted to identify mutant genes using DNA from hair follicles. Mutation impairment prediction and conservative analysis were conducted to predict the mutation impairment and structure of JAK2N533S. In addition, we conducted a functional analysis of JAK2N533S by constructing Ba/F3 cell models.
UNASSIGNED: Three distinct tumor subclones, namely JAK2N533Shet+/CALRtype1het +, JAK2N533Shet+/CALR wt, and JAK2N533Shet+/CALRtype1hom +, were identified from the 17 selected erythroid and 21 selected granulocyte colonies. The analysis of hair follicles yielded positive results for JAK2N533S. According to the bioinformatics analysis, JAK2N533S may exert only a minor effect on protein function. Functional studies showed that JAK2N533S did not have a significant effect on the proliferation of Ba/F3 cells in the absence of interleukin-3 (IL-3), similar to wild-type JAK2. Notably, there were no increased phosphorylation levels of JAK2-downstream signaling proteins, including signal transducer and activator of transcription 3 (STAT3) and STAT5, in Ba/F3 cells harboring the JAK2N533S.
UNASSIGNED: Our study revealed that the JAK2N533Shet+/CALRtype1het+ subclone was linked to a significant expansion advantage in this patient, indicating that it may contribute to the development of the ET phenotype. We further demonstrated that JAK2N533S, as a noncanonical JAK2 exon12 mutation, is a germline mutation that may not exert an effect on cell proliferation and protein function. These results and the present body of available data imply that certain noncanonical JAK2 mutations are not gain-of-function mutations leading to the development of myeloproliferative neoplasms.

UNASSIGNED: Essential thrombocythemia (ET), a myeloproliferative neoplasm (MPN), has a substantial risk of evolving into post-essential thrombocythemia myelofibrosis (post-ET MF). This study aims to establish a prediction nomogram for early prediction of post-ET MF in ET patients.
UNASSIGNED: The training cohort comprised 558 patients from 8 haematology centres between January 1, 2010, and May 1, 2023, while the external validation cohort consisted of 165 patients from 6 additional haematology centres between January 1, 2010, and May 1, 2023. Univariable and multivariable Cox regression analysis was performed to identified independent risk factors and establish a nomogram to predict the post-ET MF free survival. Both bias-corrected area under the curve (AUC), calibration curves and concordance index (C-index) were employed to assess the predictive accuracy of the nomogram.
UNASSIGNED: Multivariate Cox regression demonstrated that elevated red blood cell distribution width (RDW), elevated levels of lactate dehydrogenase (LDH) and the level of haemoglobin (Hb), a history of smoking and the presence of splenomegaly were independent risk factors for post-ET MF. The C-index displayed of the training and validation cohorts were 0.877 and 0.853. The 5 years, 10 years AUC values in training and external validation cohorts were 0.948, 0.769 and 0.978, 0.804 respectively. Bias-corrected curve is close to the ideal curve and revealed a strong consistency between actual observation and prediction.
UNASSIGNED: We developed a nomogram capable of predicting the post-ET MF free survival probability at 5 years and 10 years in ET patients. This tool helps doctors identify patients who need close monitoring and appropriate counselling.
UNASSIGNED: This research was funded by the Key R&D Program of Zhejiang (No. 2022C03137); the Public Technology Application Research Program of Zhejiang, China (No. LGF21H080003); and the Zhejiang Medical Association Clinical Medical Research special fund project (No. 2022ZYC-D09).

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UNASSIGNED: Hydroxyurea is a cytotoxic drug commonly used to treat various myeloproliferative disorders. However, prolonged oral administration of this drug may trigger skin side effects and ulcers. There are few clinical reports on treating leg ulcers caused by hydroxyurea and even fewer clinical reports on managing recurrent ulcers after treatment.
METHODS: An 87-year-old woman with essential thrombocythemia presented with a painful skin ulcer on her left calf. After failed outpatient treatment, she opted for hospitalisation for free skin grafting. Four months later, ulcers reappeared at the transplant site, leading to her readmission to the hospital. The diagnosis revealed that the leg ulcers were caused by hydroxyurea. Despite this, she persisted with hydroxyurea treatment and subsequently underwent posterior tibial artery perforator flap surgery. During the two-year follow-up, a new ulcer developed on the medial condyle of her other calf. However, no new ulcers or local pain were observed in the area where perforator flap grafting was performed.
UNASSIGNED: Leg ulcers caused by hydroxyurea are rare clinically and can easily be misdiagnosed. There is currently minimal research on ulcer recurrence after treatment. Posterior tibial perforator flaps may more effectively promote the healing of recurrent ulcers.
CONCLUSIONS: Compared to conservative treatment and skin grafting surgery, the posterior tibial artery perforator flap offers a dependable blood supply and enhances the likelihood of wound healing. It can be considered an option, particularly for recurrent and refractory ulcers, even without discontinuing medication.

UNASSIGNED: Myeloproliferative neoplasm (MPN) is a heterogeneous group of hematopoietic stem cell disorders characterized by clonal proliferation of one of more of the hematopoietic stem cell lineages. Clinical manifestations result from uncontrolled myeloproliferation, extramedullary hematopoiesis with splenomegaly and excessive inflammatory cytokine production. Currently available therapy improves hematologic parameters and symptoms but does not adequately address the underlying neoplastic biology. Bomedemstat has thus far demonstrated clinical efficacy and tolerability in the treatment of MPNs with recent evidence of impacting the malignant stem cell population.
UNASSIGNED: This review summarizes the mechanisms of action, pharmacokinetics and pharmacodynamics, safety and efficacy of bomedemstat in MPN with specific emphasis on essential thrombocythemia (ET) and myelofibrosis (MF).
UNASSIGNED: In patients with MPNs, bomedemstat appears effective and well tolerated. The signs and symptoms of these diseases are managed as a reduction in the frequency of mutant cells was demonstrated in patients with ET and MF. Ongoing and planned studies of bomedemstat in MPN will establish the position of bomedemstat in MPNs and may help to redefine treatment endpoints of MPNs in the future.