Blood and Marrow Transplantation Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612-9497, USA.
Clin Cancer Res. 2012 Nov 15;18(22):6155-68. doi: 10.1158/1078-0432.CCR-12-0531. Epub 2012 Sep 17.
In myeloma, B cells and plasma cells show a clonal relationship. Clonotypic B cells may represent a tumor-initiating compartment or cancer stem cell responsible for minimal residual disease in myeloma.
We report a study of 58 patients with myeloma at time of diagnosis or relapse. B cells in bone marrow were evaluated by multicolor flow cytometry and sorting. Clonality was determined by light chain and/or immunoglobulin chain gene rearrangement PCR. We also determined aldehyde dehydrogenase activity and colony formation growth. Drug sensitivity was tested with conventional and novel agents.
Marrow CD19+ cells express a light chain identical to plasma cells and are therefore termed light chain restricted (LCR). The LCR B-cell mass is small in both newly diagnosed and relapsed patients (≤ 1%). Few marrow LCR B cells (~10%) are CD19+/CD34+, with the rest being more differentiated CD19+/CD34- B cells. Marrow LCR CD19+ B cells exhibit enhanced aldehyde dehydrogenase activity versus healthy controls. Both CD19+/CD34+ and CD19+/CD34- cells showed colony formation activity, with colony growth efficiency optimized when stroma-conditioned medium was used. B-cell progenitors showed resistance to melphalan, lenalidomide, and bortezomib. Panobinostat, a histone deacetylase inhibitor, induced apoptosis of LCR B cells and CD138+ cells. LCR B cells are CD117, survivin, and Notch positive.
We propose that antigen-independent B-cell differentiation stages are involved in disease origination and progression in myeloma. Furthermore, investigations of myeloma putative stem cell progenitors may lead to novel treatments to eradicate the potential reservoir of minimal residual disease.
在骨髓瘤中，B 细胞和浆细胞显示出克隆关系。克隆性 B 细胞可能代表肿瘤起始区或癌干细胞，负责骨髓瘤中的微小残留病。
我们报告了 58 例骨髓瘤患者在诊断或复发时的研究。通过多色流式细胞术和分选评估骨髓中的 B 细胞。通过轻链和/或免疫球蛋白链基因重排 PCR 确定克隆性。我们还测定了醛脱氢酶活性和集落形成生长。用常规和新型药物测试药物敏感性。
骨髓 CD19+细胞表达与浆细胞相同的轻链，因此称为轻链受限（LCR）。新诊断和复发患者的骨髓 LCR B 细胞质量较小（≤1%）。骨髓 LCR B 细胞中只有少数（~10%）为 CD19+/CD34+，其余为更分化的 CD19+/CD34-B 细胞。骨髓 LCR CD19+B 细胞表现出比健康对照增强的醛脱氢酶活性。CD19+/CD34+和 CD19+/CD34-细胞均表现出集落形成活性，当使用基质条件培养基时，集落生长效率优化。B 细胞祖细胞对美法仑、来那度胺和硼替佐米具有耐药性。组蛋白去乙酰化酶抑制剂帕比司他诱导 LCR B 细胞和 CD138+细胞凋亡。LCR B 细胞 CD117、存活素和 Notch 阳性。
我们提出，抗原非依赖性 B 细胞分化阶段参与骨髓瘤的发病和进展。此外，对骨髓瘤假定的干细胞祖细胞的研究可能会导致新的治疗方法来根除微小残留病的潜在储库。
