Hematology and Hematological Malignancies, University of Utah and Veterans Administration Hospital, Salt Lake City, UT; Huntsman Cancer Institute, Salt Lake City, UT; Nuvance Health Rudy L. Ruggles Biomedical Research Institute, Danbury, CT; Department of Obstetrics, Gynecology and Reproductive Sciences, Larner College of Medicine, University of Vermont, Burlington, VT.
Hematology and Hematological Malignancies, University of Utah and Veterans Administration Hospital, Salt Lake City, UT; Huntsman Cancer Institute, Salt Lake City, UT.
Exp Hematol. 2020 Mar;83:57-65. doi: 10.1016/j.exphem.2020.01.013. Epub 2020 Jan 30.
Clonality studies can establish the single-cell origin of tumors and thus differentiate clonal malignant and premalignant processes from reactive polyclonal processes. Detection of clonal cells may be based on direct tracking of cell lineage-specific sequences or disease-specific somatic mutations identifying the clonal population. Historically, clonal hematopoiesis was defined using the principle of X-chromosome inactivation based on observation that in circulating clonal cells, only one of the active chromosomes was expressed. In myeloproliferative neoplasms (MPNs) virtually all circulating erythrocytes, platelets, and granulocytes are products of single mutated stem cells that preferentially differentiate into the myeloid rather than lymphoid lineage. Thus, clonal differentiated myeloid cells co-exist in circulation with polyclonal long-lived T lymphocytes that originated before the MPN-initiating somatic clonal event. Chronic lymphocytic leukemia (CLL) starts in a differentiating B cell, but other lymphoid lineages and myeloid cells remain polyclonal. Normal T and B cells co-exist with the CLL clone, but are diluted by the massively expanded CLL population, which outnumbers the residual normal cells. Clonal hematopoiesis of undetermined potential (CHIP) has been identified by whole-genome sequencing of healthy individuals. These clones contain a specific somatic mutation previously considered to be disease defining but are detected in only a small proportion of circulating leukocytes, and there is no obvious suppression of normal hematopoietic stem cells. However, more studies are needed to properly define these clones, their persistence or disappearance, and their relative propensity for transforming into leukemias, myeloproliferative neoplasms, or other clonal hematological malignancies.
克隆性研究可以确定肿瘤的单细胞起源，从而将克隆性恶性和癌前病变与反应性多克隆过程区分开来。克隆细胞的检测可能基于细胞谱系特异性序列的直接跟踪，或识别克隆群体的疾病特异性体细胞突变。从历史上看，克隆性造血是使用基于 X 染色体失活原理来定义的，这是基于观察到在循环的克隆细胞中，只有一条活性染色体被表达。在骨髓增生性肿瘤（MPN）中，几乎所有循环的红细胞、血小板和粒细胞都是单一突变干细胞的产物，这些干细胞优先分化为髓系而不是淋巴系。因此，循环中存在与多克隆长寿 T 淋巴细胞共存的克隆分化的髓系细胞，这些 T 淋巴细胞起源于 MPN 起始的体细胞克隆事件之前。慢性淋巴细胞白血病（CLL）起源于分化的 B 细胞，但其他淋巴系和髓系细胞仍保持多克隆性。正常 T 和 B 细胞与 CLL 克隆共存，但被大量扩增的 CLL 群体稀释，后者的数量超过了残留的正常细胞。通过对健康个体的全基因组测序，已经确定了不确定潜能的克隆性造血（CHIP）。这些克隆包含以前被认为是疾病定义的特定体细胞突变，但仅在一小部分循环白细胞中检测到，并且正常造血干细胞没有明显抑制。然而，需要更多的研究来正确定义这些克隆、它们的持续存在或消失，以及它们向白血病、骨髓增生性肿瘤或其他克隆性血液恶性肿瘤转化的相对倾向。
