The Ongoing Challenges of Managing Cytopenic Myelofibrosis in 2025: The Emergence of Non-JAK Inhibitor Therapies

A Novel Somatic Mutation in IKZF1 Is Common in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant for Myelofibrosis

Comparison of the Clinicopathological Findings of Patients with <i>SF3B1</i>/<i>JAK2</i>, <i>SF3B1</i>/<i>Calr</i>, or <i>SF3B1</i>/<i>MPL</i> co-Mutations

Outcomes of Blast-Phase MPN and JAK2, MPL, and CALR Mutated de Novo AML Compared to AML with Wild-Type JAK2, MPL, and CALR Genes: A Propensity Score-Adjusted Cohort Study

Whole Exome Sequencing Identifies Novel MPL and JAK2 M utations in Triple Negative Myeloproliferative Neoplasms

Clinicopathologic Analysis of Calr Mutation Subtypes in Myeloproliferative Neoplasms

The Genomic Landscape of Myeloproliferative Neoplasms: Somatic Calr Mutations in the Majority of JAK2-Wildtype Patients

The Frequency of Calr and MPL Gene Mutations in Jak2 V617F - Positive Chronic Myeloproliferative Neoplasms in Russia

Germline-Somatic Interactions in Myelofibrosis Susceptibility

Myeloproliferative neoplasms have a prevalence of around 350,000 in the USA and include the diagnoses of essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). These clonal neoplasms share core set of acquired driver mutations in JAK2, calreticulin (CALR), and MPL which all lead to constitutive activation of the JAK-STAT pathway. Additionally, a range of somatic mutations may occur which impact disease phenotype as risk of progression (such as ASXL1, IDH 1 &amp; 2, EZH2 2 etc). The burden of these illnesses include a predisposition to thrombosis or bleeding, a range of challenging symptoms (from spleen pain, to hypermetabolic symptoms, pruritus, fatigue, bone pain), splenomegaly, cytopenias, and potential progression to acute myeloid leukemia. Although the origin of these diseases are anchored in a clonal neoplastic process, inflammation potentially plays a role in the risk of thrombosis, the origin of many of the difficult symptoms, potential contribution to cytopenias, and the potential risk of progression from ET/PV to MF, or from MF to AML. A spectrum of cytokines have been found to be elevated in MPNs (especially in MF), with elevation of certain ones negatively impacting prognosis including IL-8, IL-2R, IL-12, IL-15. Therapy of MPNs now includes non-specific cytoreduction (i.e. hydroxyurea for ET-PV), long acting interferons (i.e. ropegylated interferon a2b for polycythemia vera), and JAK inhibition with ruxolitinib (inhibits JAK1 and JAK2), fedratinib (JAK2 and FLT3), pacritinib (inhibits JAK2, FLT3, IRAK1, and ACVR1), and momelotinib (inhibits JAK1, JAK2, ACVR1). The JAK inhibitors have made a significant impact on decreasing the burden MPN patients face by decreasing splenomegaly (and its associated symptom burden), by decreasing MPN associated symptoms, and by improving survival. The mechanism of improved survival is not fully understood but may include a decrease in marrow inflammation and perhaps decreasing the mutagenic pressure that leads to additional somatic mutations such as ASXL1 that leads to AML. Hepcidin associated with inflammation is dually being investigated as means to decrease erythrocytosis in PV with hepcidin mimetics (i.e. rusferatide), and to improve MF associated anemia by inhibiting hepcidin (momelotinib or pacritinib by ACVR1 inhibition). Inflammation as both a driver of disease burden and progression, as well as a viable therapeutic target remains an important focus of investigation and interventional trials. Citation Format: Ruben Mesa. Myeloproliferative neoplasms: Inflammation and treatment [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr IA22.

Frequent Mutations in the Calreticulin Gene CALR in Myeloproliferative Neoplasms

Dual Driver Mutant BCR-ABL1-Negative Myeloid Neoplasms: Multicenter Clinicopathologic and Genomic Analysis

Thrombophilia testing: A British Society for Haematology guideline

Background: Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPN) are a group of hematological malignancies, including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). Mutations of JAK2, CALR, MPL, and ASXL1 are associated with carcinogenesis and clinical characteristics of Ph-negative MPN. However, the availability of the data regarding these mutations is relatively limited in Thai population. Objective: To investigate these mutations in Thai Ph-negative MPN patients. Materials and Methods: One hundred thirty-six MPN (48 PV, 72 ET, and 16 PMF) cases were enrolled. Mutations of JAK2 V617F and MPL W515L/K mutations were investigated using allele-specific PCR (AS-PCR) and confirmed by sequencing. CALR and ASXL1 mutations were investigated using Sanger sequencing. Results: The JAK2 V617F mutation was detected in 83.3% of PV, 66.6% of ET, and 50.0% of PMF, and correlated with higher RBC, WBC, and PLT counts in PV. CALR mutations were detected in 16.7% of ET and 12.5% of PMF and associated with a higher PLT count in ET. The MPL W515L mutation was detected in one PMF patient. ASXL1 mutations were detected in 6.3% of PV, 8.3% of ET, and 12.4% of PMF, with c.1954G&gt;A being the preponderant mutational form. ASXL1 mutations increased the risk (RR 27.6) and accelerated the onset of AML transformation. Conclusion: The present study provided the prevalence and clinical correlation of JAK2, CALR, MPL, and ASXL1 mutations among Thai Ph-negative MPN patients. The association of ASXL1 mutations with adverse clinical outcomes suggested the potential usefulness of these mutations as a prognostic marker for Ph-negative MPN patients. Keywords: JAK2, MPL, CALR, ASXL1, Thai, Philadelphia-negative myeloproliferative neoplasm (MPN)

Calr Is up-Regulated in Patients with Essential Thrombocythemia Independently from Calr and JAK2 Mutations

Objective: A sequencing panel consisting of 50 genes was customized to reveal the potential molecular land-scapes of essential thrombocytosis, polycythemia vera, and primary myelofibrosis in Chinese patients with myeloproliferative neoplasm (MPN). Methods: Sixty-five MPN patients (38 with essential thrombocytosis, 21 with polycythemia vera, and 6 with primary myelofibrosis), including 12 triple-negative patients, were recruited and were screened for their mutational spectrum using next-generation sequencing technology in this retrospective observational study. This study was approved by the Institutional Review Board of Changhai Hospital, Naval Military Medical University, China. Results: In addition to the typical driver mutations in JAK2 , CALR , and MPL , pathogenic mutations in 15 other genes were frequently detected among the 65 patients with MPN. The 15 mutated genes were TET2, EZH2, ASXL1, MIR662, MLH1, MLH3, SF3B1, MSH6, BARD1, DNMT3A, KIT, MSH2, RUNX1, TP53 , and NRAS in this order according to the mutational frequency detected. The average number of mutated genes was 1.2 genes per patient, while in the 12 triple-negative patients with MPN (ie, patients that lack the JAK2 , CALR , or MPL mutations), at least one of the 15 pathogenic mutations was detected for each patient. Interestingly, 4 single nucleotide polymorphisms (rs4858647, rs9376092, rs58270997, rs621940) that might be correlated to individual susceptibility to myeloproliferative neoplasm were identified among the 65 patients. We also found that single nucleotide polymorphism and/or single nucleotide variation mutations occurred in multiple loci of mismatch repair-related genes, which might contribute to the development of MPN. Conclusion: Our study confirms the importance of the previously known MPN relative genes and, more importantly, provides some new and potentially valuable information about mutations associated with MPNs.