Pilarski L M, Mant M J, Belch A R
Department of Oncology, University of Alberta and Cross Cancer Institute Edmonton, Canada.
Leuk Lymphoma. 1999 Jan;32(3-4):199-210. doi: 10.3109/10428199909167381.
Myeloma is incurable because the malignant stem cell is not eradicated by treatment. Thus, identification of the malignant hierarchy of B lineage cells in myeloma is required to identify potentially generative components and to evaluate their drug resistance properties. BM plasma cells are usually depleted by chemotherapy, but clonotypic B cells survive melphalan/prednisone as well as combination chemotherapy. In vitro, circulating and bone marrow-localized myeloma plasma cells show defective drug export, despite their phenotypic expression of P-glycoprotein, the mdr1 gene product. In contrast to plasma cells, circulating myeloma clonotypic B cells exhibit very efficient drug export. This suggests that circulating clonotypic MM B cells comprise a reservoir of drug resistant disease in myeloma although their stem cell potential remains to be confirmed. The malignant clone in each myeloma patient is defined by a unique IgH VDJ gene rearrangement. Using methods that exclude the possibility that a frequent but non-malignant clone has inadvertently been identified, and after confirming that the sequence identified is expressed by nearly all bone marrow plasma cells, we show that the drug resistant set of myeloma B cells is clonally related to the malignant plasma cells in myeloma. Clonotypic MM B cells survive chemotherapy, persist during clinically defined "minimal residual disease" and remain after autologous transplantation. Thus their malignant status is an important consideration. If malignant, they must be considered in the design of therapy. If non-malignant, they would be expected to have minimal impact on the disease process. A variety of evidence provides strong support for the view that clonotypic drug resistant B cells are malignant and may include the generative compartment of myeloma. The P-gp+ set of clonotypic B cells is extensively DNA aneuploid, an attribute of malignancy. All clonotypic B cells overexpress RHAMM, a novel oncogene involved in malignant spread. Finally, the population of clonotypic B cells lacks intraclonal heterogeneity. Since intraclonal heterogeneity is driven by the response to antigens, its absence in these cells indicates that they are no longer antigen-responsive. Since antigen-independent clonal expansion is characteristic of lymphoid malignancies, these observations provide further proof that clonotypic B cells in myeloma are malignant. Thus, the drug resistance of these cells is highly relevant to understanding why myeloma remains incurable despite the initial chemosensitivity of most bone marrow plasma cells.
骨髓瘤无法治愈，因为治疗无法根除恶性干细胞。因此，需要确定骨髓瘤中B淋巴细胞的恶性层级，以识别潜在的增殖成分并评估其耐药特性。骨髓浆细胞通常会被化疗清除，但克隆型B细胞在美法仑/泼尼松以及联合化疗后仍能存活。在体外，尽管循环和骨髓定位的骨髓瘤浆细胞表面表达P-糖蛋白（mdr1基因产物），但其药物外排功能存在缺陷。与浆细胞不同，循环骨髓瘤克隆型B细胞表现出非常高效的药物外排。这表明循环克隆型骨髓瘤B细胞构成了骨髓瘤耐药疾病的一个储存库，尽管其干细胞潜能仍有待证实。每个骨髓瘤患者的恶性克隆由独特的IgH VDJ基因重排定义。通过排除意外鉴定出常见但非恶性克隆的可能性，并在确认鉴定出的序列几乎由所有骨髓浆细胞表达后，我们发现骨髓瘤B细胞的耐药群体与骨髓瘤中的恶性浆细胞存在克隆相关性。克隆型骨髓瘤B细胞在化疗后存活，在临床定义的“微小残留病”期间持续存在，并在自体移植后仍留存。因此，它们的恶性状态是一个重要的考量因素。如果是恶性的，在治疗设计中就必须予以考虑。如果是非恶性的，预计它们对疾病进程的影响极小。各种证据有力支持了克隆型耐药B细胞是恶性的这一观点，并且它们可能包含骨髓瘤的增殖部分。克隆型B细胞的P-gp+群体存在广泛的DNA非整倍体现象，这是恶性肿瘤的一个特征。所有克隆型B细胞均过度表达RHAMM，这是一种参与恶性扩散的新型癌基因。最后，克隆型B细胞群体缺乏克隆内异质性。由于克隆内异质性是由对抗原的反应驱动的，这些细胞中缺乏克隆内异质性表明它们不再对抗原产生反应。由于不依赖抗原的克隆性扩增是淋巴恶性肿瘤的特征，这些观察结果进一步证明骨髓瘤中的克隆型B细胞是恶性的。因此，这些细胞的耐药性与理解为何尽管大多数骨髓浆细胞最初对化疗敏感，但骨髓瘤仍无法治愈高度相关。
