Stemness of B-cell progenitors in multiple myeloma bone marrow.
Stemness of B-cell progenitors in multiple myeloma bone marrow.
复制标题
多发性骨髓瘤骨髓中B细胞祖细胞的干性。
DOI：
10.1158/1078-0432.ccr-12-0531
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发表时间：
2012-11-15
期刊：
影响因子：
--
通讯作者：
Perez LE
中科院分区：
文献类型：
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作者：
Boucher K;Parquet N;Widen R;Shain K;Baz R;Alsina M;Koomen J;Anasetti C;Dalton W;Perez LE
在骨髓瘤中，B细胞和浆细胞显示出克隆关系。克隆型B细胞可能代表肿瘤起始区室或负责骨髓瘤中微小残留疾病的癌症干细胞。我们报告了58例骨髓瘤患者在诊断或复发时的研究。骨髓B细胞用流式细胞仪和分选仪检测。通过轻链和/或免疫球蛋白链基因重排PCR确定克隆性。我们还测定了乙醛脱氢酶活性和菌落形成生长。药物敏感性测试与传统的和新的代理。骨髓CD 19+细胞表达与浆细胞相同的轻链，因此称为轻链限制性（LCR）。新诊断和复发患者的LCR B细胞群均较小（≤1%）。少数骨髓LCR B细胞（~10%）为CD 19 +/CD 34+，其余为分化程度更高的CD 19 +/CD 34 − B细胞。与健康对照相比，骨髓LCR CD 19 + B细胞表现出增强的醛脱氢酶活性。CD 19 +/CD 34+和CD 19 +/CD 34 −细胞均表现出集落形成活性，当使用基质条件培养基时，集落生长效率得到优化。B细胞祖细胞显示对美法仑、来那度胺和硼替佐米的耐药性。Panobinostat是一种组蛋白去乙酰化酶抑制剂，可诱导LCR B细胞和CD 138+细胞凋亡。LCR B细胞为CD 117、生存素和Notch阳性。我们认为抗原非依赖性B细胞分化阶段参与了骨髓瘤的发生和发展。对骨髓瘤假定的干细胞祖细胞的进一步研究可能会导致新的治疗方法，以根除潜在的微小残留疾病。
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. Further investigations of myeloma putative stem cell progenitors may lead to novel treatments to eradicate the potential reservoir of minimal residual disease.