Autoimmunity and persistent RAS- mutated clones long after the spontaneous regression of JMML
Autoimmunity and persistent RAS- mutated clones long after the spontaneous regression of JMML
复制标题
JMML 自发消退后很长时间内的自身免疫和持续性 RAS 突变克隆
作者：
Takagi M;Imai C;et al
少年髓单细胞白血病（JMML）是一种慢性侵袭性儿童髓系白血病。患者表现为肝脾肿大，白细胞增多伴单核细胞增多，可浸润脾、肝和肺。约80%的JMML患者白血病细胞存在遗传异常，包括NF1、NRAS、KRAS、CBL或PTPN11的突变。偶有报道称JMML病例的临床和实验室结果与自身免疫性疾病相符。我们和Niemela等人最近提出了一种新的疾病实体，称为RALD （ras相关的自身免疫淋巴增殖性综合征（ALPS）样疾病）。3,4在涉及T、B和髓系的造血干细胞分化的一定水平上，RALD表现出与获得性RAS突变相关的alps样临床表型。鉴于RAS-MAPK信号通路共同异常的遗传特征和不同的预后特征，RALD和JMML是否可以通过其临床和生物学特征来区分，这是一个重要的问题。在本研究中，我们收集并分析了6例日本患者的临床和实验室特征，这些患者符合与RAS突变相关的JMML的临床和实验室标准，并在没有进行造血干细胞移植（HSCT）的情况下随访了3年以上。5-8他们在表型上不同于心-面-皮综合征或努南综合征。虽然他们在最初表现时符合JMML的诊断标准，包括骨髓祖细胞的粒细胞-巨噬细胞集落刺激因子（GM-CSF）超敏（表1和补充表1），但疾病消退后未见疾病进展或复发。随访期在3到19年之间。这些患者的体格检查发现1例持续性肝脾肿大（病例6，补充表2）。这6例患者的实验室数据显示白细胞计数正常，除了1例（病例4）持续单核细胞增多症（补充表2）。淋巴细胞群T/B比均显示B细胞群增加40%以上。有趣的是，6例中有4例显示高γ-球蛋白血症（图1a和表2），6例中有5例显示自身免疫抗体阳性（表2），主要是抗核抗体。病例3和6表现为持续性自身免疫性血小板减少。病例6也出现贫血。因此，该患者极有可能患有埃文斯综合征。病例2符合系统性红斑狼疮的诊断标准。这些观察结果与RALD的结果一致。因此，我们研究了这6名患者在疾病消退多年后，其造血系统中是否继续携带RAS突变。
Juvenile myelomonocytic leukemia (JMML) is a chronic and aggressive myeloid leukemia in children. Patients show hepatosplenomegaly, and leukocytosis associated with monocytosis that can infiltrate the spleen, liver and lungs. About 80% of patients with JMML have a genetic abnormality in their leukemia cells, including mutations of NF1, NRAS, KRAS, CBL or PTPN11. 1 Occasionally JMML cases have been reported to be associated with clinical and laboratory findings compatible with autoimmune disease. 2 We and Niemela et al. 3 recently proposed a novel disease entity known as RALD (RAS-associated autoimmunelymphoproliferative syndrome (ALPS)-like disease). 3, 4 RALD shows ALPS-like clinical phenotypes associated with acquired RAS mutation at certain levels of hematopoietic stem cell differentiation involving the T, B and myeloid lineages. Given the shared genetic features of common abnormality of the RAS-MAPK signaling pathway but distinct prognostic features, an important question arises as to whether RALD and JMML can be discriminated by their clinical and biological characteristics.In the present work, we collected and analyzed the clinical and laboratory characteristics of six Japanese patients fulfilling the clinical and laboratory criteria of JMML associated with RAS mutation and followed for more than 3 years without hematopoietic stem cell transplantation (HSCT). 5–8 They are phenotypically distinct from patients with Cardio-Facio-Cutaneous syndrome or Noonan syndrome. Although they fulfilled the diagnostic criteria of JMML at the initial presentation, including granulocyte-macrophage colony-stimulating factor (GM-CSF) hyper-sensitivity of bone marrow progenitors (Table 1 and Supplementary Table 1), no disease progression or recurrence was seen after regression of the disease. The follow-up periods were between 3 and 19 years. Physical examination of these patients identified one case with persistent hepatosplenomegaly (Case 6, Supplementary Table 2). Laboratory data of these six patients exhibited normal white blood cell counts, except for one case (Case 4) with persistent monocytosis (Supplementary Table 2). T/B ratio of lymphocyte population showed increased B cell population of more than 40% in all the cases. Interestingly, four of six cases showed hyper-γ-globulinemia (Figure 1a, and Table 2) and five of the six cases showed positivity for autoimmune antibodies (Table 2), mainly that for antinuclear antibody. Cases 3 and 6 presented persistent autoimmune thrombocytopenia. Case 6 also presented anemia. Thus, this patient was very likely to have had Evans syndrome. Case 2 fulfilled the diagnostic criteria for systemic lupus erythematosus. These observations were compatible with the findings in RALD. So we investigated whether these six patients continued to carry RAS mutation in their hematopoietic systems many years after disease regression.