Bone marrow hematopoietic dysfunction in untreated chronic lymphocytic leukemia patients.
Bone marrow hematopoietic dysfunction in untreated chronic lymphocytic leukemia patients.
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未治疗的慢性淋巴细胞性白血病患者的骨髓造血功能障碍。
DOI：
10.1038/s41375-018-0280-0
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发表时间：
2019-03
期刊：
影响因子：
11.4
通讯作者：
Medina KL
中科院分区：
文献类型：
--
作者：
Manso BA;Zhang H;Mikkelson MG;Gwin KA;Secreto CR;Ding W;Parikh SA;Kay NE;Medina KL
b -慢性淋巴细胞白血病（CLL）免疫功能障碍的后果可能与困扰CLL患者的严重复发感染和二次恶性肿瘤的发生率有关。描述良好的免疫异常不能一致地解释这些并发症。在这里，我们报告了早期和晚期未经治疗的CLL患者的骨髓（BM）造血功能障碍。在标准CFU检测（包括CFU- gm /GEMM和CFU- e）中，应答的CD34+ BM造血祖细胞数量显著减少。流式细胞术显示CLL患者骨髓中所有造血干细胞和祖细胞（HSPC）亚群的频率相应降低。与HSPCs的减少一致，BM驻留的单核细胞和自然杀伤（NK）细胞也减少了，这一缺陷在血液中重现。最后，我们报道了CLL患者BM中转录调节因子HIF-1α GATA-1、PU.1和GATA-2蛋白水平的增加，为HSPC功能障碍的分子基础提供了见解。重要的是，当健康的HSPCs体外暴露于TNFα（一种由CLL B细胞组成的细胞因子）时，PU.1和GATA-2迅速增加。总之，这些发现揭示了未经治疗的CLL患者的骨髓造血功能障碍，为CLL复杂免疫缺陷状态的病因提供了新的见解。
The consequences of immune dysfunction in B-Chronic Lymphocytic Leukemia (CLL) likely relate to the incidence of serious recurrent infections and second malignancies that plague CLL patients. The well-described immune abnormalities are not able to consistently explain these complications. Here, we report bone marrow (BM) hematopoietic dysfunction in early and late stage untreated CLL patients. Numbers of CD34+ BM hematopoietic progenitors responsive in standard CFU assays, including CFU-GM/GEMM and CFU-E, were significantly reduced. Flow cytometry revealed corresponding reductions in frequencies of all hematopoietic stem and progenitor cell (HSPC) subsets assessed in CLL patient marrow. Consistent with the reduction in HSPCs, BM resident monocytes and natural killer (NK) cells were reduced, a deficiency recapitulated in blood. Finally, we report increases in protein levels of the transcriptional regulators HIF-1α GATA-1, PU.1, and GATA-2 in CLL patient BM, providing molecular insight into the basis of HSPC dysfunction. Importantly, PU.1 and GATA-2 were rapidly increased when healthy HSPCs were exposed in vitro to TNFα, a cytokine constitutively produced by CLL B cells. Together, these findings reveal BM hematopoietic dysfunction in untreated CLL patients that provides new insight into the etiology of the complex immunodeficiency state in CLL.
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影响因子：
14.9
作者：
Bresnick EH;Katsumura KR;Lee HY;Johnson KD;Perkins AS
通讯作者：
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影响因子：
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Grigorakaki, Christine;Morceau, Franck;Diederich, Marc
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Ferrara, N
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Lotz, M;Ranheim, E;Kipps, T J
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Kipps, T J
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作者：
Koczula, K. M.;Ludwig, C.;Guenther, U. L.
通讯作者：
Guenther, U. L.