肿瘤细胞治疗研究
英文原题：Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome: A case report and review of literature.
播散性结核可诱导骨髓中CD56+淋巴细胞浸润，进而抑制正常和白血病性造血，导致再生障碍性危象和白血病细胞消退。
骨髓增生异常综合征（MDS）由恶性增殖和无效造血引起。致癌性体细胞突变以及凋亡、坏死性凋亡和焦亡增加导致早期造血祖细胞积累和成熟血细胞生成受损。原始粒细胞百分比增加和不良体细胞突变的存在是白血病性造血的标志，也是进入晚期阶段的指标。骨髓细胞量和原始粒细胞通常随疾病进展而增加。然而，晚期MDS偶尔会发生再生障碍危象。病例摘要：一名72岁男性患者，根据原始粒细胞和分化簇（CD）34+造血祖细胞百分比增加，以及骨髓样本中鉴定出髓系肿瘤相关体细胞突变，被明确诊断为伴原始细胞过多-1的MDS（MDS-EB-1）。该患者接受去甲基化治疗，并能够维持疾病稳定状态2年。在治疗过程中，该晚期MDS患者经历了一次进行性全血细胞减少和骨髓再生障碍发作。在再生障碍危象期间，骨髓被稀疏分布的非典型淋巴细胞浸润。令人惊讶的是，白血病细胞消失了。免疫学分析显示，非典型淋巴细胞高频率表达CD3、CD5、CD8、CD16、CD56和CD57，提示自身免疫性细胞毒性T淋巴细胞和自然杀伤（NK）/NKT细胞活化，抑制了正常和白血病性造血。包括白细胞介素（IL）-6、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）在内的炎性细胞因子血清水平升高，证实了I型免疫反应的紊乱。这种形态学和免疫学特征导致了继发于大颗粒淋巴细胞白血病的重型再生障碍性贫血的诊断。在寻找炎症病灶的放射学检查中，怀疑为播散性结核。抗结核治疗导致再生障碍性危象逆转、非典型淋巴细胞消失、骨髓细胞增多以及2个月的血液学缓解，提供了强有力的证据，表明播散性结核是再生障碍性危象发生、白血病细胞消退和CD56+非典型淋巴细胞激活的原因。在随后的19个月中重新开始低甲基化治疗，使患者得以维持稳定的疾病状态。然而，患者疾病表型转化为急性髓系白血病，最终死于疾病进展和压倒性的感染事件。
BACKGROUND: Myelodysplastic syndrome (MDS) is caused by malignant proliferation and ineffective hematopoiesis. Oncogenic somatic mutations and increased apoptosis, necroptosis and pyroptosis lead to the accumulation of earlier hematopoietic progenitors and impaired productivity of mature blood cells. An increased percentage of myeloblasts and the presence of unfavorable somatic mutations are signs of leukemic hematopoiesis and indicators of entrance into an advanced stage. Bone marrow cellularity and myeloblasts usually increase with disease progression. However, aplastic crisis occasionally occurs in advanced MDS. CASE SUMMARY: A 72-year-old male patient was definitively diagnosed with MDS with excess blasts-1 (MDS-EB-1) based on an increase in the percentages of myeloblasts and cluster of differentiation (CD)34+ hematopoietic progenitors and the identification of myeloid neoplasm-associated somatic mutations in bone marrow samples. The patient was treated with hypomethylation therapy and was able to maintain a steady disease state for 2 years. In the treatment process, the advanced MDS patient experienced an episode of progressive pancytopenia and bone marrow aplasia. During the aplastic crisis, the bone marrow was infiltrated with sparsely distributed atypical lymphocytes. Surprisingly, the leukemic cells disappeared. Immunological analysis revealed that the atypical lymphocytes expressed a high frequency of CD3, CD5, CD8, CD16, CD56 and CD57, suggesting the activation of autoimmune cytotoxic T-lymphocytes and natural killer (NK)/NKT cells that suppressed both normal and leukemic hematopoiesis. Elevated serum levels of inflammatory cytokines, including interleukin (IL)-6, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), confirmed the deranged type I immune responses. This morphological and immunological signature led to the diagnosis of severe aplastic anemia secondary to large granule lymphocyte leukemia. Disseminated tuberculosis was suspected upon radiological examinations in the search for an inflammatory niche. Antituberculosis treatment led to reversion of the aplastic crisis, disappearance of the atypical lymphocytes, increased marrow cellularity and 2 mo of hematological remission, providing strong evidence that disseminated tuberculosis was responsible for the development of the aplastic crisis, the regression of leukemic cells and the activation of CD56+ atypical lymphocytes. Reinstitution of hypomethylation therapy in the following 19 mo allowed the patient to maintain a steady disease state. However, the patient transformed the disease phenotype into acute myeloid leukemia and eventually died of disease progression and an overwhelming infectious episode. CONCLUSION: Disseminated tuberculosis can induce CD56+ lymphocyte infiltration in the bone marrow and in turn suppress both normal and leukemic hematopoiesis, resulting in the development of aplastic crisis and leukemic cell regression.
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