期刊
BLOOD
卷 120, 期 13, 页码 2620-2630出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-04-347484
关键词
-
类别
资金
- Leukamie Liga e.V., Dusseldorf, Germany
- Forschungskommission of the Heinrich-Heine-University, Dusseldorf, Germany
- American Society of Hematology-European Hematology Association (ASH-EHA) research exchange award
- EHA research fellowship
- National Cancer Institute
- Leukemia Research Foundation
Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGF beta signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term self-renewal were impaired as a consequence of activated TGF beta signaling. In accordance, TGF beta levels in the BM extracellular fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capacity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGF beta signaling. Furthermore, we found defective actin assembly and down-regulation of the adhesion receptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myeloma-free NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which underlines that functional impairment of HSPCs depends on MM-related microenvironmental cues and is reversible. Taken together, these data implicate that hematopoietic suppression in MM emerges from the HSPCs as a result of MM-related microenvironmental alterations. (Blood. 2012; 120(13):2620-2630)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据