JAK2 Mutation Research Articles

Myeloid Sarcoma of Conjunctiva in a patient with JAK2-positive myeloid neoplasm: two distinct myeloid neoplasms sequentially arising from a common precursor

Abstract Introduction/Objective Myeloid sarcoma (aka granulocytic sarcoma or chloroma), a rare type of myeloid neoplasm is characterized by the presence of myelogenous blastic cells outside of the bone marrow either before, during or after the development of leukemia. Presentation in the orbit is extremely rare, unlike other body parts. We report a case of myeloid sarcoma of conjunctiva in a patient with JAK2-positive myeloid neoplasm. Methods/Case Report An 84-year-old man presented with bilateral conjunctival masses which on biopsy showed diffuse involvement by blasts, immunohistochemically expressing positivity for myeloperoxidase, CD33, CD68, CD34 (partial), CD117 (partial) but were non-reactive to CD15, CD3 and PAX5. Next generation sequencing (NGS) revealed mutations in NRAS, ASXl1 and TET2 genes, consistent with the diagnosis of myeloid sarcoma (MS) of the conjunctiva. While patient’s past medical history included status post radiation and chemotherapy for prostate cancer and colonic adenocarcinoma respectively. it was also significant for a JAK 2 positive myeloproliferative neoplasm (MPN), six-years prior to current presentation. At the time he was treated with hydroxyurea for 5 years but developed neutrophilic leukocytosis and transfusion-dependent anemia. Subsequently a treatment regimen including ruxolitinib and pacritinib was initiated but without clinical and hematological improvements. NGS of the initial JAK2-positive MPN revealed ASXL1, JAK2 and TET2 mutations. Of note are the similarities and variations in the molecular signatures of patient’s initial MPN and current conjunctival MS. While the two neoplasms carried an identical TET2 mutation with highest variant allelic frequency, they are different in other mutations. Results (if a Case Study enter NA) NA Conclusion Our case illustrates an unusual manifestation of myeloid sarcoma localized to the conjunctiva. The identification of clonal relatedness on NGS with distinct mutations, adds complexity to our understanding of tumor origin. It highlights a series of events which may have contributed to this phenomenon, including consequence of therapy, clonal evolution with molecular discordance or origin as a totally independent entity. This report underscores the importance of genetic profiling in guiding prognosis and treatment strategies in such settings.

Cerebral venous sinus thrombosis associated with JAK2 V617F mutation-related pre-primary myelofibrosis: a case report and literature review

BackgroundCerebral venous sinus thrombosis (CVST) is a rare but potentially life-threatening subtype of stroke. Prompt and appropriate anticoagulation is crucial for improving the prognosis of CVST and preventing its recurrence. Identifying the underlying cause of CVST is decisive for guiding anticoagulant selection and determining treatment duration.Case PresentationA 50-year-old man presented with a 35-day history of headache, nausea, vomiting, and blurred vision. Digital subtraction angiography performed at another facility revealed CVST. A contrast-enhanced black-blood MRI at our center confirmed the diagnosis, which was supported by a high intracranial pressure of 330mmH2O. Laboratory tests showed elevated leukocytes and platelet counts, raising suspicion of an underlying myeloproliferative neoplasms (MPNs). A bone marrow biopsy demonstrated increased megakaryocytes and granulocytes, and genetic testing identified the presence of the Janus kinase 2 V617F (JAK2 V617F) mutation, leading to a diagnosis of pre-primary myelofibrosis (pre-PMF). During hospitalization, anticoagulation with nadroparin calcium and fibrinolytic therapy were initiated. Upon discharge, rivaroxaban and aspirin were prescribed to prevent CVST recurrence and arterial thrombosis.ConclusionThis case highlights the importance of recognizing dynamic changes in routine blood tests that may link CVST to underlying hematological disorders. The JAK2 mutation is not only associated with MPNs but also increases the risk of thrombosis, including CVST. Further investigation is warranted to better understand the mechanisms by which JAK2 mutations contribute to thrombosis and to explore the potential benefits of JAK2 inhibitors in reducing this risk.

JAK2 mutational status and the contribution of TERT and JAK2 polymorphisms to the occurrence of myeloproliferative neoplasms in Eastern Morocco

Background: The JAK2 V617F somatic mutation is a hallmark of myeloproliferative neoplasms (MPN) and is present in some patients with splanchnic venous thrombosis (SVT). Objectives: We investigated for the first time in Eastern Morocco the JAK2 mutational status and germline risk factors, such as the TERT and JAK2 polymorphisms, in MPN and SVT patients. Methods: This study included 38 patients with MPN, 24 patients presenting with SVT and 60 healthy donors from the BRO Biobank. JAK2 mutations were analyzed using qPCR and Sanger sequencing. Predisposing polymorphisms to MPN were evaluated using Sanger sequencing. Results: JAK2 V617F mutation was positive in 64.5% of patients with MPN and 20.8% of patients with SVT. The JAK2 V617F allelic burden ranged from 2% to 97.53%. We found a strong association between the JAK2 rs56241661 polymorphism of the JAK2 46/1 haplotype and the development of MPN. However, no association was detected between the TERT rs2736100 polymorpism and MPN. Conclusion: The JAK2 mutational status and its allelic burden in Eastern Morocco are consistent with previous studies. The JAK2 46/1 haplotype was strongly associated with MPN. However, unlike other previously studied populations, the TERT polymorphism rs2736100 has no effect on the occurrence of MPN in our population. Keywords: Myeloproliferative neoplasms; JAK2 V617F; TERT and JAK2 polymorphisms; genetic predisposition; Morocco.

Relation of JAK2 V617F allele burden and coronary calcium score in patients with essential thrombocythemia.

JAK2 V617F (JAK2) mutation is associated with clonal hemopoiesis in myeloproliferative neoplasms as well as with faster progression of cardiovascular diseases. Little is known about the relationship between allele burden and the degree of atherosclerotic alteration of coronary vasculature. We previously reported that carotid artery stiffness progressed faster in patients with JAK2 positive essential thromocythemia (ET) patients. After a four-year follow-up we investigated whether mutation burden of a JAK2 allele correlates with a higher coronary calcium score. Thirty-six patients with JAK2 positive ET and 38 healthy matched control subjects were examined twice within four years. At each visit clinical baseline characteristics and laboratory testing were performed, JAK2 mutation burden was determined, and coronary calcium was measured. JAK2 allele burden decreased in 19 patients, did not change in 5 patients, and increased in 4 patients. The coronary calcium Agatston score increased slightly in both groups. Overall, there was no correlation between JAK2 allele burden and calcium burden of coronary arteries. However, in patients with the JAK2 mutation burden increase, the coronary calcium score increased as well. The average JAK2 allele burden decreased in our patients with high-risk ET during the four-year period. However, in the small subgroup whose JAK2 mutation burden increased the Agatston coronary calcium score increased as well. This finding, which should be interpreted with caution and validated in a larger group, is in line with emerging evidence that JAK2 mutation accelerates atherosclerosis and can be regarded as a non-classical risk factor for cardiovascular disease.

Synergistic effect of concurrent high molecular risk mutations and lower JAK2 mutant variant allele frequencies on prognosis in patients with myelofibrosis-insights from a multicenter study.

In addition to high-molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH, and U2AF1Q157), lower JAK2V617F variant allele frequencies (VAF) have been demonstrated to be associated with poor prognosis of myelofibrosis (MF) patients. Nevertheless, the relationship between JAK2V617F VAF and HMR mutations remains inconclusive. To address this, we analyzed the mutation status of 54 myeloid neoplasm-relevant genes using targeted next-generation sequencing in 124 MF patients. Three cohorts from multiple international centers were analyzed for external validation. Among JAK2-mutated patients, the presence of HMR mutations drove poor prognosis in patients with lower JAK2V617F VAF but not in those with higher JAK2V617F VAF. Survival analyses showed consistent results across validation cohorts. In multivariable analysis, concurrent HMR and a lower JAK2V617F VAF was identified as an independent adverse prognostic factor for survival, irrespective of age, MIPSS70, MIPSS70 + v2, and GIPSS risk groups. Mutation co-occurrence tests revealed no shared mutational pattern over different cohorts, excluding potential confounding effect from other concurrent mutations. Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics.

B-191 Genomic Profile of Circulating Tumor DNA in Advanced Lung Cancer: Comparison with Tissue DNA

Abstract Background The most common cancer in Korea is thyroid cancer, followed by lung cancer, and the most common cancer in men is lung cancer. The cancer with the highest mortality rate is lung cancer. Recently, the precision medical approach is becoming a major treatment strategy for lung cancer. For precision medical approach, the usefulness of next-generation sequencing (NGS) analysis targeting circulating tumor DNA (ctDNA) is being emphasized. Therefore, in this study, NGS analysis was performed on blood and tissues of advanced lung cancer patients to compare and analyze genetic mutation patterns to confirm the usefulness of ctDNA NGS assay. Methods A total of 101 patients with advanced lung cancer (stage 3 or 4) were recruited, and ctDNA NGS assays were performed on their plasma using a Pan100 panel (Dxome). Tissues from primary lung cancer, metastatic lymph nodes, or metastatic organs of 22 patients were analyzed using ONCOaccuPanel (NGeneBio). All variants were classified into four tiers based on the level of clinical significance, according to the standards and guidelines established by the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. Results In the ctDNA NGS assay of 101 patients, 70 (69.3%) harbored 154 tier 1 or 2 variants. Mutations in TP53 (45, 29.2%) and EGFR (23, 14.9%) were the most frequently detected, followed by mutations in RB1, CHEK2, ATM, JAK2, ATR, DNMT3A, and KRAS. Among the 22 patients whose tissue was examined, tier 1 or 2 variants were detected in both the plasma and tissue of 14 patients and only in the tissue of six patients. All genes for these variants were targeted using both methods. Identical variants were detected in the plasma and tissue of six of the 14 patients, and discordant results were observed in the remaining eight patients. Twenty copy number variations were detected in 13 of the 101 patients, with copy number gain of EGFR being the most common (6, 30%). Fusion genes were detected in five of the 101 patients, two of which were not detected in the tissue. Overall, 74 (73.3%) of the 101 patients had positive ctDNA NGS assay results. Conclusions Although the NGS assay with ctDNA is less sensitive than that with tissue DNA, some genetic alterations are detected only in ctDNA NGS assays; therefore, it is useful to apply the ctDNA NGS assay as a complement.

JAK2 Mutation Assessment in Thrombotic Events at Unusual Anatomical Sites: Insights from a High-Altitude Cohort.

Thrombosis stands as a significant contributor to both morbidity and mortality in individuals afflicted with myeloproliferative neoplasms. This retrospective study investigated the association between JAK2 mutations and venous thrombosis at unusual sites, and in young individuals with ischemic stroke, residing at high altitudes in the Aseer region, Saudi Arabia. Data were collected from two high-altitude referral hospitals over three years (2020-2022). Records of all JAK2 mutation tests were reviewed. Those requested as part of evaluation of thrombosis events, without known myeloproliferative neoplasms (MPNs) were analysed. Among the 208 JAK2 tests, 40 (19.2%) were linked to thrombotic event evaluations. The cohort, with a median age of 41, included 17 (42.7%) males and 23 females, with 57.5% having completely normal complete blood counts (CBC). Thrombotic events were divided between splanchnic vein thrombosis (36.6%) and cerebral thrombosis (34.1%), while the remaining cases involved unprovoked deep vein thromboses/pulmonary embolisms and portal vein thrombosis. Only 2 (5%) participants tested positive for JAK2 mutations: a 17-year-old male diagnosed concurrently with polycythemia vera after renal vein thrombosis and a 31-year-old woman with hepatic vein thrombosis and a normal CBC. This study reveals that JAK2 mutations are infrequently found in high-altitude patients with unprovoked DVT, PE, or atypical thrombosis. While JAK2 testing is notably relevant for splanchnic vein thrombosis, its routine use for other thrombotic events, particularly with normal CBC results, remains uncertain. Given the study's limitations, further prospective research with larger cohorts is needed to refine guidelines for JAK2 mutation testing in various thrombotic contexts.

Differential modulation of mutant CALR and JAK2 V617F-driven oncogenesis by HLA genotype in myeloproliferative neoplasms.

It has been demonstrated previously that human leukocyte antigen class I (HLA-I) and class II (HLA-II) alleles may modulate JAK2 V617F and CALR mutation (CALRmut)-associated oncogenesis in myeloproliferative neoplasms (MPNs). However, the role of immunogenetic factors in MPNs remains underexplored. We aimed to investigate the potential involvement of HLA genes in CALRmut+ MPNs. High-resolution genotyping of HLA-I and -II loci was conducted in 42 CALRmut+ and 158 JAK2 V617F+ MPN patients and 1,083 healthy controls. A global analysis of the diversity of HLA-I genotypes revealed no significant differences between CALRmut+ patients and controls. However, one HLA-I allele (C*06:02) showed an inverse correlation with presence of CALR mutation. A meta-analysis across independent cohorts and healthy individuals from the 1000 Genomes Project confirmed an inverse correlation between the presentation capabilities of the HLA-I loci for JAK2 V617F and CALRmut-derived peptides in both patients and healthy individuals. scRNA-Seq analysis revealed low expression of TAP1 and CIITA genes in CALRmut+ hematopoietic stem and progenitor cells. In conclusion, the HLA-I genotype differentially restricts JAK2 V617F and CALRmut-driven oncogenesis potentially explaining the mutual exclusivity of the two mutations and differences in their presentation latency. These findings have practical implications for the development of neoantigen-based vaccines in MPNs.

Ruxolitinib combined with venetoclax and azacitidine in the treatment of refractory T-ALL patients with JAK1, JAK3, and STAT5B gene mutations: a case report and literature review

Refractory acute T-lymphoblastic leukemia (T-ALL), which is characterized by a low sensitivity to conventional induction therapy and poor prognosis, poses significant challenges during treatment. This study reported a case of refractory T-ALL patient with mutations in the JAK1, JAK3, and STAT5B genes from Nanjing University's Gulou Hospital. Following an unsuccessful course of standard VDLP regimen chemotherapy, the treatment was modified to include ruxolitinib in combination with venetoclax and azacitidine. Subsequent to this therapy, the patient achieved bone marrow minimal residual disease (MRD) negativity. Notably, pleural effusion and mediastinal mass significantly improved the post-chest cavity infusion of dexamethasone combined with etoposide at the same stage. The patient also underwent allogeneic hematopoietic stem cell transplantation upon achieving bone marrow remission and was followed up until January 2024. Ruxolitinib combined with venetoclax and azacytidine has shown promising efficacy and safety in treating refractory T-ALL harboring the JAK1, JAK3, and STAT5B mutations, providing a novel therapeutic approach for such patients.

Clinical and genetic profile of Chinese patients with indolent natural killer-cell lymphoproliferative disorder of the gastrointestinal tract

Indolent natural killer cell lymphoproliferative disorder of the gastrointestinal tract (iNKLPD-GI) is an uncommon, recently recognized lymphoid proliferation of mature NK cells primarily manifesting in the GI tract. Unlike NK/T lymphoma, iNKLPD-GI exhibits a rather indolent clinical course, underscoring the need for cautious management to prevent unnecessary interventions. However, clinical and molecular features of this entity have not been thoroughly understood. This study aimed to add more information to the current knowledge of this disease. Seven patients with iNKLPD-GI were included in our study. Clinical data included initial symptoms, endoscopic manifestations, pathological features, and therapies. Besides, next-generation sequencing was arranged to explore the underlying genetic mechanism of this disease. In our study, iNKLPD-GI in the urinary bladder was first identified. Edema of extremities (3, 42.8 %) was the most prevalent onset symptom which was reported for the first time. Pathological and immunohistological features were found to display the phenotype of NK cells. Unlike extranodal NK/T cell lymphoma, Epstein-Barr virus-encoded small RNA (EBER) were negative in all patients. Moreover, we found that two patients harbored JAK3 mutation. Apart from JAK3 K563_C565del previously reported in the literature, we discovered new JAK3 mutation sites. Other mutations including BRAF, KRAS, and SH2B3 were also identified. In conclusion, iNKLPD-GI was an indolent atypical NK-cell proliferation with diverse clinical characteristics. “Watch and wait” therapy was preferable to intense chemotherapy. Recurrent JAK3 mutation may be the underlying mechanism responsible for the neoplastic nature of the disease and may serve as a potential target for patients with severe symptoms.

Transformation into acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 from JAK2-mutated essential thrombocythemia: a case report

BackgroundBlast 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.Case presentationThe 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.ConclusionsTo 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.

Potential biomarkers and immune characteristics for polycythemia vera-related atherosclerosis using bulk RNA and single-cell RNA datasets: a combined comprehensive bioinformatics and machine learning analysis.

Polycythemia vera (PV) is a myeloproliferative disease characterized by significantly higher hemoglobin levels and positivity for JAK2 mutation. Thrombosis is the main risk event of this disease. Atherosclerosis (AS) can markedly increase the risk of arterial thrombosis in patients with PV. The objectives of our study were to identify potential biomarkers for PV-related AS and to explore the molecular biological association between PV and AS. We extracted microarray datasets from the Gene Expression Omnibus (GEO) dataset for PV and AS. Common differentially expressed genes (CGs) were identified by differential expression analysis. Functional enrichment and protein-protein interaction (PPI) networks were constructed from the CG by random forest models using LASSO regression to identify pathogenic genes and their underlying processes in PV-related AS. The expression of potential biomarkers was validated using an external dataset. A diagnostic nomogram was constructed based on potential biomarkers to predict PV-related AS, and its diagnostic performance was assessed using ROC, calibration, and decision curve analyses. Subsequently, we used single-cell gene set enrichment analysis (GSEA) to analyze the immune signaling pathways associated with potential biomarkers. We also performed immune infiltration analysis of AS with "CIBERSORT" and calculated Pearson's correlation coefficients for potential biomarkers and infiltrating immune cells. Finally, we observed the expression of potential biomarkers in immune cells based on the single-cell RNA dataset. Fifty-two CGs were identified based on the intersection between up-regulated and down-regulated genes in PV and AS. Most biological processes associated with CGs were cytokines and factors associated with chemotaxis of immune cells. The PPI analysis identified ten hub genes, and of these, CCR1 and MMP9 were selected as potential biomarkers with which to construct a diagnostic model using machine learning methods and external dataset validation. These biomarkers could regulate Toll-like signaling, NOD-like signaling, and chemokine signaling pathways associated with AS. Finally, we determined that these potential biomarkers had a strong correlation with macrophage M0 infiltration. Further, the potential biomarkers were highly expressed in macrophages from patients with AS. We identified two CGs (CCR1 and MMP9) as potential biomarkers for PV-related AS and established a diagnostic model based on them. These results may provide insight for future experimental studies for the diagnosis and treatment of PV-related AS.

Impact of JAK2 V617F mutation on disease profile and prognostic risk factors in primary myelofibrosis (MPN) - A tertiary care experience.

Objective: To evaluate the association between JAK2 mutation status, PMF disease characteristics, and prognostic features as assessed by the DIPSS Plus scoring system. We analyzed clinical and laboratory data from a cohort of PMF patients to determine the influence of JAK2 mutation on disease presentation and progression. Study Design: Cross Sectional study. Setting: Department of Pathology and Oncology, King Edward Medical University/Mayo Hospital, Lahore. Period: December 2022 to December 2023. Methods: Total 27 patients with PMF were enrolled in the study by non-probability consecutive sampling technique. Patients were diagnosed according to WHO 2016 criteria. CBC and serum LDH were performed by automated hematology and chemistry analyzers respectively. Real-time PCR was used to identify the JAK2 mutations. Risk stratification was done by DIPPS criteria. Data was analyzed by Microsoft Excel 2010. Mean and standard deviation was calculated. Student ‘T’ test was used for comparison of mean between two groups with and without JAK2 mutations. Results: Out of 27 patients 66.6% were males and median age was 59 years. Splenomegaly was the dominant clinical feature accounting for 51.4% with mean splenic span of 17.8±2.91cm. Mean LDH levels was 872.5±324. JAK2 positive expression was found to be significantly correlated with increased splenic span and raised LDH levels with P-value of <0.05. Risk stratification showed 11% patients were in high-risk group. Conclusion: Marked enlargement of spleen and raised in serum LDH levels indicate that patients in our settings had clinically advanced stage of the disease. Apart from this manifestation of JAK2 V617F mutated patients indicated a more aggressive phenotype of the disease.

Molecular biomarkers of leukemia: convergence-based drug resistance mechanisms in chronic myeloid leukemia and myeloproliferative neoplasms.

Leukemia represents a diverse group of hematopoietic neoplasms that can be classified into different subtypes based on the molecular aberration in the affected cell population. Identification of these molecular classification is required to identify specific targeted therapeutic approaches for each leukemic subtype. In general, targeted therapy approaches achieve good responses in some leukemia subgroups, however, resistance against these targeted therapies is common. In this review, we summarize molecular drug resistance biomarkers in targeted therapies in BCR::ABL1-driven chronic myeloid leukemia (CML) and JAK2-driven myeloproliferative neoplasms (MPNs). While acquisition of secondary mutations in the BCR::ABL1 kinase domain is the a common mechanism associated with TKI resistance in CML, in JAK2-driven MPNs secondary mutations in JAK2 are rare. Due to high prevalence and lack of specific therapy approaches in MPNs compared to CML, identification of crucial pathways leading to inhibitor persistence in MPN model is utterly important. In this review, we focus on different alternative signaling pathways activated in both, BCR::ABL1-mediated CML and JAK2-mediated MPNs, by combining data from in vitro and in vivo-studies that could be used as potential biomarkers of drug resistance. In a nutshell, some common similarities, especially activation of PDGFR, Ras, PI3K/Akt signaling pathways, have been demonstrated in both leukemias. In addition, induction of the nucleoprotein YBX1 was shown to be involved in TKI-resistant JAK2-mediated MPN, as well as TKI-resistant CML highlighting deubiquitinating enzymes as potential biomarkers of TKI resistance. Taken together, whole exome sequencing of cell-based or patients-derived samples are highly beneficial to define specific resistance markers. Additionally, this might be helpful for the development of novel diagnostic tools, e.g., liquid biopsy, and novel therapeutic agents, which could be used to overcome TKI resistance in molecularly distinct leukemia subtypes.

Predictive significance of high neutrophil ratio for thrombosis in myeloproliferative neoplasms: JSH-MPN-R18 subanalysis.

Thrombosis in myeloproliferative neoplasms (MPNs) is an important clinical problem, and risk-stratified management is essential. To identify the clinical characteristics of thrombosis in patients with MPNs, a nationwide multi-institutional retrospective analysis (JSH-MPN-R18) was conducted. The aim of the present study was to perform a sub-analysis of JSH-MPN-R18 findings to clarify the predictive parameters for thrombosis among complete blood count (CBC) results. Among the patients enrolled in JSH-MPN-R18, those with essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456) were investigated. We analyzed and compared CBC parameters between patients with and those without any thrombotic events using Welch's T-test. Statistical analyses were performed using the R statistical software. Thrombotic events were observed in 74 patients with ET. In multivariate analysis, only the neutrophil ratio was slightly but significantly higher for ET patients with thrombosis than for those without (p < 0.05). Of note, the absolute neutrophil count (aNeu) was considered a useful predictive tool for thrombosis among patients classified as low-risk according to the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia. Among PV patients, those with thrombosis showed significantly higher hematocrit and aNeu than did those without thrombosis. As a thrombosis-associated factor, the neutrophil ratio was slightly but significantly elevated in patients with ET. This myeloid skew might reflect a higher value of JAK2 V617F allelic frequency in patients with ET with thrombosis; this was not clarified in JSH-MPN-R18. Further accumulation of evidence, including genetic information for JAK2 and other passenger mutations, is warranted.

JAK2-mutant clonal hematopoiesis is associated with venous thromboembolism

AbstractVenous thromboembolism (VTE) is common among older individuals, but provoking factors are not identified in many cases. Patients with myeloid malignancies, especially myeloproliferative neoplasms (MPNs), are at increased risk for venous thrombosis. Clonal hematopoiesis of indeterminate potential (CHIP), a precursor state to myeloid malignancies, is common among older individuals and may similarly predispose to venous thrombosis. We evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400 000 samples from the UK Biobank. CHIP was modestly associated with incident VTE with a hazard ratio (HR) of 1.17 (95% confidence interval [CI], 1.09-1.3; P = .002) but was not significantly associated with prevalent VTE with an odds ratio (OR) of 1.02 (95% CI, 0.81-1.23; P = .81). TET2-mutant CHIP was associated with incident VTE with a HR of 1.33 (95% CI, 1.05-1.69; P = .02). JAK2 mutations were highly associated with both prevalent and incident VTE risk, with an OR of 6.58 (95% CI, 2.65-16.29; P = 4.7 × 10–5) and a HR of 4.2 (95% CI, 2.18-8.08; P = 1.7 × 10–5), respectively, consistent with the thrombophilia associated with JAK2-mutant MPN. The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed MPN based on laboratory parameters. JAK2-mutant CHIP was more strongly associated with VTE but was less common than heterozygous factor V Leiden and heterozygous prothrombin gene mutation. These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but individuals with JAK2-mutant CHIP have a significantly elevated risk of VTE.

Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia.

Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies. Despite these insights, the exact roles of circadian rhythms, sphingosine-1-phosphate (S1P), stromal cell-derived factor-1 (SDF-1), sterile inflammation, and the complement cascade on various BM niche cells remain inadequately understood. Further research is needed to elucidate how BM niche cells contribute to these malignancies through neural regulation and their potential in the development of gene-corrected stem cells. This literature review describes the updated functional aspects of BM niche cells in haematopoiesis within the context of haematological malignancies, with a particular focus on neural signaling and the potential of radiomitigators in acute radiation syndrome. Additionally, it underscores the pressing need for technological advancements in stem cell-based therapies to alleviate the impacts of immunological stressors. Recent studies have illuminated the microheterogeneity and temporal stochasticity of niche cells within the BM during haematopoiesis, emphasizing the updated roles of neural signaling and immunosurveillance. The development of gene-corrected stem cells capable of producing blood, immune cells, and tissue-resident progeny is essential for combating age-related haematological malignancies and overcoming immunological challenges. This review aims to provide a comprehensive overview of these evolving insights and their implications for future therapeutic strategies.

Polyglobulie secondaire chez un fumeur français de chicha

AbstractThe diagnosis of polycythemia, particularly to distinguish primary from secondary causes, can be challenging. Biological criteria associated with a detailed anamnesis are essential to explore secondary polycythemia. Several causes may be involved, tobacco being one of the most common.We describe the case of a 46-old French man from Cape Verde with suffer from polycythemia and a high level of carboxyhemoglobin. The JAK2 mutation (V617F) was absent and the EPO level was high. The patient had no clinical symptoms. The anamnesis ruled out a daily habit of smoking shisha. After one month without smoking, blood counts and carboxyhaemoglobin completely normalized, confirming the hypothesis of polycythemia secondary to carbon monoxide intoxication from shisha smoke.

Simultaneous portal vein thrombosis and splenic vein thrombosis in a COVID-19 patient: A case report and review of literature

BACKGROUND It is well-described that the coronavirus disease 2019 (COVID-19) infection is associated with an increased risk of thrombotic complications. While there have been many cases of pulmonary emboli and deep vein thrombosis in these patients, reports of COVID-19 associated portal vein thrombosis (PVT) have been uncommon. We present a unique case of concomitant PVT and splenic artery thrombosis in a COVID-19 patient. CASE SUMMARY A 77-year-old-male with no history of liver disease presented with three days of left-sided abdominal pain. One week earlier, the patient was diagnosed with mildly symptomatic COVID-19 and was treated with nirmatrelvir/ritonavir. Physical exam revealed mild right and left lower quadrant tenderness, but was otherwise unremarkable. Significant laboratory findings included white blood cell count 12.5 K/μL, total bilirubin 1.6 mg/dL, aminoaspartate transferase 40 U/L, and alanine aminotransferase 61 U/L. Computed tomography of the abdomen and pelvis revealed acute PVT with thrombus extending from the distal portion of the main portal vein into the right and left branches. Also noted was a thrombus within the distal portion of the splenic artery with resulting splenic infarct. Hypercoagulable workup including prothrombin gene analysis, factor V Leiden, cardiolipin antibody, and JAK2 mutation were all negative. Anticoagulation with enoxaparin was initiated, and the patient’s pain improved. He was discharged on apixaban. CONCLUSION It is quite uncommon for PVT to present simultaneously with an arterial thrombotic occlusion, as in the case of our patient. Unusual thrombotic manifestations are classically linked to hypercoagulable states including malignancy and hereditary and autoimmune disorders. Viral infections such as Epstein-Barr virus, cytomegalovirus, viral hepatitis, and COVID-19 have all been found to increase the risk of splanchnic venous occlusions, including PVT. In our patient, prompt abdominal imaging led to early detection of thrombus, early treatment, and an excellent outcome. This case is unique in that it is the second known case within the literature of simultaneous PVT and splenic artery thrombosis in a COVID-19 patient.

Momelotinib - a promising advancement in the management of myelofibrosis in adults with anemia.

Myelofibrosis (MF) is a rare BCR-ABL negative myeloproliferative neoplasm characterized by clonal proliferation of stem cells, with mutations in JAK2, CALR, or MPL genes. MF presents in primary and secondary forms, with common symptoms including splenomegaly, anemia, and thrombocytopenia. Diagnostic criteria involve bone marrow examination and mutation studies. Current treatments are limited, with allogeneic stem cell transplant as the only curative option. Recent FDA approval of Momelotinib (MMB) offers new promise for MF patients with anemia. MMB, a JAK1/2 and ACVR1 inhibitor, effectively reduces spleen size, improves hemoglobin levels, and decreases transfusion dependency. The MOMENTUM trial compared MMB to danazol in JAK inhibitor-treated MF patients with anemia, showing MMB's superior symptom relief and transfusion independence rates. Additionally, the SIMPLIFY-1 and SIMPLIFY-2 trials evaluated MMB in JAK inhibitor-naïve and experienced patients, respectively, confirming MMB's non-inferiority to ruxolitinib in spleen volume reduction and highlighting its benefits in transfusion requirements. MMB's unique dual inhibition mechanism addresses anemia by suppressing hepcidin production, thus enhancing erythropoiesis. These trials collectively suggest MMB as an effective treatment for MF, improving quality of life and offering a survival advantage for patients with anemia. Despite challenges, such as trial design limitations and adverse events, MMB represents a significant advancement in MF management, providing a new therapeutic option for a previously underserved patient population.