2023年 · 第103卷第45期

Abnormal pro-inflammatory cytokine signaling is a feature of cancer. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm (MPN) characterized by somatic symptoms, progressive erythropenia, splenomegaly, and an increased risk of evolving into acute leukemia. Dominant myelofibrosis (MF) can also evolve from prefibrous MPN, including polycythemia vera (PV) and essential thrombocythemia (ET). Dysregulation of inflammatory signaling is one of the important reasons leading to the progression of MPN fibrosis. Previous studies have shown that the JAK/STAT and TNF-α/NF-κ B inflammatory pathways jointly promote fibrosis progression in MPN patients, however, how a single cytokine triggers fibrosis and clonal evolution in malignant MPN cells has not been fully elucidated.

Myeloproliferative tumors (MPN) are a group of hematopoietic stem progenitor cell malignant proliferative tumors characterized by uncontrolled expansion of bone marrow cells, elevated blood count, and a high risk of progression to secondary acute myeloid leukemia (sAML). In the majority of patients, mutations in the key MPN-related driver gene (JAK2/CALR/MPL) were detected. The World Health Organization (WHO) classification identifies 3 classical MPNs: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Each of these MPN subtypes exhibits unique clinical, morphological, and molecular characteristics. Despite presenting as hematopoietic stem progenitor cell malignancies, little is known about the disease-causing stem progenitors in MPN.

The study aimed to explore the risk factors that influence the development of thrombotic events in patients with myelofibrosis (sMF) secondary to polycythemia vera (PV) /essential thrombocythemia (ET). The study assessed the incidence and risk factors for thrombosis in 1 258 sMF patients with a median follow-up of 3.5 years, with driver mutations in 1 203 (95.6%) patients, JAK2 mutations in 100% of PPV-MF, JAK2 mutations in 54% (319) of PET-MF, CALR mutations in 191 (33%) and MPL mutations in 52 (9.7%). Fifty-six percent (466/830) and 16% (155/958) of patients received cell-lowering drugs (CT) or JAKi drugs. Of the 466 patients treated with CT, 315 (67.6%) received hydroxyurea (HU), 67 (14.3%) received HU-based combination therapy, and of the 155 patients treated with JAKi medication, 135 (87%) received ruxolitinib (RUX) and 8 (5%) received Rux-based combination therapy. By the time of follow-up, 604 (48%) patients had died, with an annual mortality rate of 9.4%. Prior to the onset of sMF, thrombotic events occurred in 279 (22.2%) patients, including 158 (25.7%) with PV and 121 (18.8%) with ET (P=0.003), 135 (10.7%) patients experienced thrombotic events at a median follow-up time of 3.5 years, with an annual incidence rate of 2.3%.

Myeloproliferative tumors (MPN) are sporadic in most cases, and some germline gene mutations, such as TET-2, TERT, ATG2B/GSKIP, MECOM, HBS1L-MYB and RBBP6, may cause a small number of familial MPN cases. However, the pathogenic germline mutations in most familial MPN cases are unknown.

Myeloproliferative neoplasms (MPN) are a class of diseases that are at high risk of transforming into myelofibrosis (MF) and acute myeloid leukemia (AML). The mechanisms and targets for intervention in their progression are still unclear. The study found that the high mobility group protein A1 (HMGA1) chromatin regulator acts as a participating factor in JAK2^V617FAn epigenetic switch for the progression of mutant MPN, revealing that HMGA1 may serve as a new therapeutic target for MPN.