iAMPlified gene expression offers new insights in B cell precursor leukemia subtype.
iAMPlified gene expression offers new insights in B cell precursor leukemia subtype.
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iAMPlified 基因表达为 B 细胞前体白血病亚型提供了新的见解。
DOI：
10.1080/10428194.2019.1695055
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发表时间：
2020
影响因子：
2.6
通讯作者：
Ntziachristos,Panagiotis
中科院分区：
文献类型：
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作者：
Ntziachristos,Panagiotis
急性淋巴细胞白血病（ALL）是最常见的儿童癌症，约占15岁以下儿童癌症诊断的25%。在美国，每年约有6000名儿童和青少年被诊断为ALL，并且发病率呈逐渐上升趋势。虽然目前的治疗方法，包括全身化疗和放疗，显示出相对较高的反应率（高达80%），但它们可能是负担，并具有继发性恶性肿瘤的高风险。复发和难治性患者的治疗选择很少。使用工程化T细胞的免疫疗法对一些患者似乎很有希望，但这些实验性疗法表现出一些毒性。因此，由于目前治疗的毒性，缺乏靶向治疗，以及这种疾病的侵袭性复发病例，ALL代表了一个高度未满足的需求。ALL患者表现为几种血液谱系的抑制，包括导致瘀伤的血小板减少症、导致疲劳的贫血症和导致感染的中性粒细胞减少症。转移到中枢神经系统和睾丸也很常见。虽然约80%的儿童ALL患者对化疗有反应（标准风险），但无反应（难治性疾病）或化疗后复发（高风险）的患者生存可能性有限。临床、免疫表型和细胞遗传学标记已被用于疾病预后。例如，诊断时的高母细胞数量、化疗期间母细胞的持续存在或化疗期间的快速复发（表现为克隆或微小残留疾病的检测，MRD）、t细胞免疫表型和染色体数量较少（次二倍体）与疾病预后不良相关。ALL患者在诊断时约有20个基因改变事件。易位常与预后有关。例如，费城染色体t (9; 22)（q34; q11）的存在与预后不良相关，而RUNX融合体如t (12; 21)(p13; q22)/ETV6-RUNX1与预后良好相关。21号染色体染色体内扩增（iAMP21）存在于2%的儿童b细胞前体ALL （BCP-ALL）病例中，于2003年首次发现[2,3]，被认为是该疾病亚型[4]的原发事件，诊断时患者中位年龄为9岁，预后中差。事实上，这些病例在接受标准化疗时预后较差，而对积极化疗方案反应良好。尽管iAMP21由包括多个获得区、扩增区、逆转区和缺失区在内的异质谱改变组成，但使用FISH检测单个异常21号染色体上的四个或更多RUNX1拷贝（每个细胞共有五个或更多RUNX1信号）是检测iAMP21的一种手段，因为RUNX1属于21号染色体32.8 - 37.9 m的5.1 Mb区，iAMP21很少与BCR-ABL1或ETV6-RUNX1易位共存。然而，RUNX1在该疾病亚型中的作用迄今尚未明确，令人惊讶的是，与其他21号染色体异常的病例相比，iAMP21病例中RUNX1的表达并没有特别升高。这种疾病亚型基本上没有得到充分的研究。
Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and represents approximately 25% of cancer diagnoses among children younger than 15years. About 6000 children and adolescents are diagnosed with ALL each year in the US and there is a gradual increase in the incidence [1]. Although current treatments, including systemic chemotherapy and radiation, show relatively high response rates (up to 80%), they can be burdensome with high risk of secondary malignancies. Relapsed and refractory patients have few treatment options. Immunotherapy using engineered T cells appears promising for some patients, but these experimental therapies exhibit some toxicity. Thus, ALL represents a highly unmet need due to the toxicity of current therapy, the absence of targeted therapies, and the aggressive relapsed cases of this disease. Patients with ALL present with a suppression of several blood lineages including thrombocytopenia that causes bruising, anemia that can cause fatigue, and neutropenia leading to infections. Metastasis to the central nervous system and testicles is also common. Although about 80% of children ALL patients respond to chemotherapy (standard risk), the patients that do not respond (refractory disease) or relapse post chemotherapy (high risk) have limited possibility for survival. Clinical, immunophenotypic, and cytogenetic markers have been used for the disease prognosis. For instance, high blast number at diagnosis, persistence of blasts during or fast reemergence during chemotherapy (manifested as the detection of clones or minimal residual disease, MRD), T-cell immunephenotype, and lower number of chromosomes (hypodiploidy) associate with poor disease prognosis. Patients with ALL present with about 20 genetic alteration events at the time of diagnosis [1].Translocations frequently associate with prognosis. For instance, the presence of the Philadelphia chromosome t (9; 22)(q34; q11) associates with poor prognosis, whereas RUNX fusions such as t (12; 21)(p13; q22)/ETV6-RUNX1 associate with good prognosis. Intrachromosomal amplification of chromosome 21 (iAMP21) exists in 2% of pediatric cases of B-cell precursor ALL (BCP-ALL), it was first detected in 2003 [2, 3], is considered a primary event in this disease subtype [4], and it is associated with a median patient age of 9years at the time of diagnosis and intermediate to poor prognosis. Indeed, these cases have poor prognosis when treated with standard chemotherapy whereas respond well to aggressive chemotherapy protocols [5]. Although iAMP21 consists of heterogeneous spectrum of alterations including multiple regions of gain, amplification, inversion, and deletion, detection of four or more copies of RUNX1 on a single abnormal chromosome 21 (a total of five or more RUNX1 signals per cell) using FISH is a means of detection of iAMP21, as RUNX1 belongs to the commonly amplified 5.1 Mb region of chromosome 21 from 32.8 to 37.9 M. iAMP21 can rarely co-exist with BCR-ABL1, or ETV6-RUNX1 translocations. Nevertheless, the role of RUNX1 in this disease subtype is not hitherto characterized and surprisingly RUNX1 expression is not particularly elevated in iAMP21 cases compared to other cases with chromosome 21 abnormalities. This disease subtype is substantially understudied.