Clonal Expansion and Interrelatedness of Distinct B-Lineage Compartments in Multiple Myeloma Bone Marrow
Clonal Expansion and Interrelatedness of Distinct B-Lineage Compartments in Multiple Myeloma Bone Marrow
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DOI：
10.1158/2326-6066.cir-17-0012
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发表时间：
2017-09-01
影响因子：
10.1
通讯作者：
Davis，Mark M.
中科院分区：
文献类型：
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作者：
Hansmann，Leo;Han，Arnold;Davis，Mark M.
多发性骨髓瘤的特征是骨髓中恶性浆细胞的克隆性扩张。但表型多样性和不太占优势的B系克隆对该病生物学的贡献一直存在争议。在这里，我们询问携带显性多发性骨髓瘤免疫球蛋白重排的细胞是否占据了浆细胞以外的表型隔室。为了实现这一目标，我们将13个参数的FACS指数排序和t-随机邻近嵌入(t-SNE)可视化与高通量单细胞免疫球蛋白测序相结合，以跟踪人类B细胞发育的不同阶段的选定B系克隆。正如预期的那样，优势克隆优先映射到异常的浆细胞隔间，尽管表型从野生型改变。有趣的是，优势克隆中高达1.2%的细胞与正常表型的B系细胞共存。此外，在高达9%的测序细胞中检测到具有不同免疫球蛋白序列的次要克隆，但这些克隆中只有2个表现出异常的免疫表型。这些小克隆中的大多数在CDR3中表现出克隆内沉默的核苷酸差异，并在免疫球蛋白基因中显示不同频率的体细胞突变。因此，骨髓中多发性骨髓瘤细胞的表型范围并不局限于异常表型的浆细胞，而是延伸到正常表型B细胞的低频率，这与最近报道的B细胞靶向细胞治疗在一些患者中的成功是一致的。大多数小克隆是由平行的非恶性扩张引起的。癌症免疫研究；©2017 AACR。
Multiple myeloma is characterized by the clonal expansion of malignant plasma cells in the bone marrow. But the phenotypic diversity and the contribution of less predominant B-lineage clones to the biology of this disease have been controversial. Here, we asked whether cells bearing the dominant multiple myeloma immunoglobulin rearrangement occupy phenotypic compartments other than that of plasma cells. To accomplish this, we combined 13-parameter FACS index sorting and t-Stochastic Neighbor Embedding (t-SNE) visualization with high-throughput single-cell immunoglobulin sequencing to track selected B-lineage clones across different stages of human B-cell development. As expected, the predominant clones preferentially mapped to aberrant plasma cell compartments, albeit phenotypically altered from wild type. Interestingly, up to 1.2% of cells of the predominant clones colocalized with B-lineage cells of a normal phenotype. In addition, minor clones with distinct immunoglobulin sequences were detected in up to 9% of sequenced cells, but only 2 out of 12 of these clones showed aberrant immune phenotypes. The majority of these minor clones showed intraclonal silent nucleotide differences within the CDR3s and varying frequencies of somatic mutations in the immunoglobulin genes. Therefore, the phenotypic range of multiple myeloma cells in the bone marrow is not confined to aberrant-phenotype plasma cells but extends to low frequencies of normal-phenotype B cells, in line with the recently reported success of B cell–targeting cellular therapies in some patients. The majority of minor clones result from parallel nonmalignant expansion.Cancer Immunol Res; 5(9); 744–54. ©2017 AACR.