The Pathogenesis, Diagnosis, And Treatment Of Systemic Mast Cell Disorders

系统性肥大细胞疾病的发病机制、诊断和治疗

• 批准号: 7964210
• 负责人: Dean D Metcalfe
• 金额: $ 42.22万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964210
• 关键词: Abdomen; Address; Adult; Angiotensin II; Biological Assay; Bone Marrow; Bone Pain; Bone marrow biopsy; Cell Count; Child; Child Care; Childhood; Chronic Disease; Chymase; Clinical; Clinical Markers; Clinical Trials; Consensus; Cutaneous; Data; Diagnosis; Diarrhea; Diffuse Cutaneous Mastocytosis; Disease; Disease Outcome; Disease regression; Fatigue; Flushing; Genes; Genetic Polymorphism; Human; Imatinib; Indolent; JAK2 gene; Laboratories; Life; Literature; Marrow; Migraine; Molecular Abnormality; Mutation; Myeloproliferative disease; Onset of illness; Pathogenesis; Patients; Peptide Hydrolases; Point Mutation; Proto-Oncogene Protein c-kit; RAS Family Gene; Receptor Protein-Tyrosine Kinases; Reporting; Role; Serine; Serotonin; Serum; Severity of illness; Specimen; Staining method; Stains; Symptoms; Systemic Mastocytosis; Systemic disease; Therapeutic; Tyrosine Kinase Inhibitor; Urticaria Pigmentosa; Whole Blood; aggressive therapy; base; clinical efficacy; disease classification; experience; improved; in vitro activity; inhibitor/antagonist; mast cell; mastocytosis; novel; outcome forecast; prognostic; thrombocytosis

Systemic mastocytosis, a clonal myeloproliferative disease with variable clinical manifestations, is associated in most cases with the D816V mutation in KIT. The identification of the KIT D816V mutation in patients with systemic mastocytosis has gained a major prognostic significance in the last several years, largely because of the availability of tyrosine kinase receptor inhibitors such as imatinib. Imatinib was shown to be ineffective in patients carrying KIT D816V mutation, but effective in cases displaying some other c-kit mutations. Activating mutations in JAK2 (JAK2 V617F) and the RAS gene family are associated with myeloproliferative diseases. We continue to screen adult patients with mastocytosis for mutations in these genes. Acquired heterozygous activating point mutations in NRAS were identified in two patients with aggressive forms of systemic mastocytosis (2/10, 20%). NRAS mutations were absent in patients with indolent disease. One indolent patient with thrombocytosis (1/14; 7%) harbored a heterozygous JAK2 V617F point mutation. Most agents in clinical trials for aggressive mastocytosis target KIT and, despite potent in vitro activity, have displayed modest clinical efficacy. Therefore, the finding of activating mutations with the potential to cooperate in disease pathogenesis has significant therapeutic implications. Pediatric onset mastocytosis usually presents as urticaria pigmentosa; and less often as diffuse cutaneous mastocytosis. While the literature indicates that disease often resolves, there has been a move to more aggressive therapy for mastocytosis early in life. We addressed the long term prognosis of pediatric-onset disease by examining 17 children with mastocytosis which we had reported on in 1989. We successfully contacted 15 of these patients and data was collected regarding their clinical status. Original bone marrow specimens were re-stained, re-examined, and correlated with disease outcome using consensus criteria. Three of five patients with persistent disease underwent repeat bone marrow biopsies. There was complete regression of disease as defined by cutaneous findings and symptoms (clinical disease severity) in 10 of 15 patients (67%). Three patients had major (20%) and two had partial regression of disease (13%). Repeat marrow examinations on three patients with persistent disease documented systemic mastocytosis based on marrow findings in one patient who had partial regression of disease and was the only patient with initial morphologic evidence of systemic disease. Of the remaining two patients, one demonstrated partial regression and the other major regression of disease; and neither had evidence of systemic mastocytosis. This study demonstrates that initial bone marrow biopsies were prognostic in that those without evidence of systemic disease experienced disease regression; and that the long term prognosis for children managed symptomatically with mastocytosis is highly encouraging. We continue to assess new clinical markers for systemic mastocytosis. As serotonin has been implicated in the genesis of clinical symptoms found in association with some chronic diseases, we determined the whole blood serotonin levels in 29 patients diagnosed with mastocytosis, and correlated these levels with multiple clinical and laboratory parameters. Patients with lower serotonin values had significantly greater rates of fatigue, migraine headaches, psychiatric symptoms, diarrhea, flushing, and abdominal and bone pain. Human chymase is a highly efficient angiotensin II-generating serine peptidase expressed by mast cells. A novel and sensitive assay was utilized to determine serum chymase levels in mastocytosis patients. Native chymase activity was detected in the serum of most subjects with systemic mastocytosis. Identification of these clinical markers in mastocytosis may help with disease classification, determining prognosis and improved treatment options.

全身性肥大细胞增多症是一种临床表现多变的克隆性骨髓增生性疾病，在大多数情况下与KIT中的D816V突变有关。在过去几年中，鉴定全身性肥大细胞增多症患者的KIT D816V突变具有重要的预后意义，这主要是因为酪氨酸激酶受体抑制剂如伊马替尼的可用性。伊马替尼对携带KIT D816V突变的患者无效，但对显示其他c-kit突变的病例有效。