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.

系统性肥大细胞增多症是一种临床表现多样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。在过去的几年里，在系统性肥大细胞增多症患者中鉴定KIT D816V突变具有重要的预后意义，这在很大程度上是因为酪氨酸激酶受体抑制剂如伊马替尼的存在。伊马替尼对携带KIT D816V突变的患者无效，但对表现出其他一些c-KIT突变的患者有效。 JAK2(JAK2 V617F)和RAS基因家族的激活突变与骨髓增生性疾病相关。我们继续筛查患有肥大细胞增多症的成年患者这些基因的突变。在2例侵袭型系统性肥大细胞增多症患者中发现了NRAS获得性杂合激活点突变(2/10，20%)。在惰性疾病患者中，NRAS基因突变缺失。1例懒惰的血小板增多症患者(1/14；7%)携带JAK2 V617F杂合点突变。大多数药物处于侵袭性肥大细胞增多症靶标试剂盒的临床试验中，尽管在体外具有很强的活性，但显示出适度的临床疗效。因此，发现在疾病发病机制中具有协同作用的激活突变具有重要的治疗意义。 儿童起病的肥大细胞增多症通常表现为色素性荨麻疹，较少表现为弥漫性皮肤肥大细胞增多症。虽然文献表明疾病通常是可以解决的，但对于早期肥大细胞增多症，已经有了更积极的治疗方法。我们通过检查17名患有肥大细胞增多症的儿童来探讨儿科疾病的长期预后，这是我们在1989年报道的。我们成功地联系了其中15名患者，并收集了有关他们临床状态的数据。使用共识标准对原始骨髓样本进行重新染色、重新检查，并与疾病转归相关。5名持续性疾病患者中有3名接受了重复的骨髓活检。根据皮肤表现和症状(临床疾病严重程度)，15名患者中有10名(67%)疾病完全消退。3例患者病情加重(20%)，2例病情部分消退(13%)。对三名持续性疾病患者进行了重复的骨髓检查，根据一名患者的骨髓检查结果，证实了系统性肥大细胞增多症，这名患者的病情部分消退，是唯一一名具有系统性疾病初始形态证据的患者。在剩下的两名患者中，一名患者表现为部分消退，另一名患者的病情明显消退；两名患者都没有系统性肥大细胞增多症的证据。这项研究表明，最初的骨髓活检可以预测预后，因为那些没有全身疾病证据的人经历了疾病回归；而对患有肥大细胞增多症的症状进行治疗的儿童的长期预后是非常令人鼓舞的。 我们继续评估系统性肥大细胞增多症的新的临床标志物。由于5-羟色胺与某些慢性疾病相关的临床症状的发生有关，我们测定了29例肥大细胞增多症患者的全血5-羟色胺水平，并将其与多项临床和实验室指标相关联。5-羟色胺水平较低的患者疲倦、偏头痛、精神症状、腹泻、脸红、腹痛和骨痛的发生率显著增加。 人凝乳酶是肥大细胞表达的一种高效的血管紧张素II生成丝氨酸肽酶。采用一种新的灵敏的方法来检测肥大细胞增多症患者的血清糜酶水平。大多数系统性肥大细胞增多症患者的血清中都检测到了天然的凝乳酶活性。识别肥大细胞增多症的这些临床标志物可能有助于疾病分类、确定预后和改进治疗方案。