Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Pathology, National Hospital Organization, Kumamoto Medical Center, Kumamoto, Japan.
Lab Invest. 2014 Nov;94(11):1212-23. doi: 10.1038/labinvest.2014.110. Epub 2014 Sep 8.
The bone marrow microenvironment, known as 'hematopoietic stem cell niche,' is essential for the survival and maintenance of hematopoietic stem cells. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases, which eventually result in leukemic transformation (acute myelogenous leukemia with myelodysplasia-related changes, AML-MRC). However, the precise components and functions of the MDS niche remain unclear. Recently, CXCL12-abundant reticular cells were shown to act as a hematopoietic stem cell niche in the murine bone marrow. Using immunohistochemistry, we show here that CXCL12(+) cells were located in the cellular marrow or perivascular area, and were in contact with CD34(+) hematopoietic cells in control and MDS/AML-MRC bone marrow. MDS bone marrow exhibited higher CXCL12(+) cell density than control or AML, not otherwise specified (AML-NOS) bone marrow. Moreover, AML-MRC bone marrow also exhibited higher CXCL12(+) cell density than control bone marrow. CXCL12(+) cell density correlated positively with bone marrow blast ratio in MDS cases. CXCL12 mRNA level was also higher in MDS bone marrow than in control or AML-NOS bone marrow. In vitro coculture analysis revealed that overexpression of CXCL12 in stromal cells upregulated BCL-2 expression of leukemia cell lines. Triple immunostaining revealed that the CD34(+) hematopoietic cells of MDS bone marrow in contact with CXCL12(+) cells were BCL-2-positive and TUNEL-negative. In the bone marrow of MDS cases, CXCL12-high group showed significantly higher Bcl-2(+)/CD34(+) cell ratio and lower apoptotic cell ratio than CXCL12-low group. Moreover, CXCL12-high refractory cytopenia with multilineage dysplasia (RCMD) cases had a greater tendency to progress to refractory anemia with excess blasts (RAEBs) or AML-MRC than CXCL12-low RCMD cases. These results suggest that CXCL12(+) cells constitute the niche for CD34(+) hematopoietic cells, and may be associated with the survival/antiapoptosis of CD34(+) hematopoietic cells and disease progression in MDS. Thus, CXCL12(+) cells may represent a novel MDS therapeutic target.
骨髓微环境，又称“造血干细胞龛”，对造血干细胞的存活和维持至关重要。骨髓增生异常综合征（MDS）是一组克隆性造血干细胞疾病，最终导致白血病转化（伴 MDS 相关改变的急性髓系白血病，AML-MRC）。然而，MDS 龛的精确组成和功能仍不清楚。最近，CXCL12 丰富的网状细胞被证明在小鼠骨髓中充当造血干细胞龛。我们通过免疫组织化学显示，在这里 CXCL12(+)细胞位于细胞骨髓或血管周围区域，并与对照和 MDS/AML-MRC 骨髓中的 CD34(+)造血细胞接触。MDS 骨髓中的 CXCL12(+)细胞密度高于对照或非特指性 AML（AML-NOS）骨髓。此外，AML-MRC 骨髓中的 CXCL12(+)细胞密度也高于对照骨髓。MDS 病例中的 CXCL12(+)细胞密度与骨髓原始细胞比例呈正相关。MDS 骨髓中的 CXCL12mRNA 水平也高于对照或 AML-NOS 骨髓。体外共培养分析显示，基质细胞中 CXCL12 的过表达上调了白血病细胞系的 BCL-2 表达。三重免疫染色显示，与 CXCL12(+)细胞接触的 MDS 骨髓中的 CD34(+)造血细胞呈 BCL-2 阳性和 TUNEL 阴性。在 MDS 病例的骨髓中，CXCL12 高组的 Bcl-2(+)/CD34(+)细胞比例明显高于 CXCL12 低组，凋亡细胞比例明显低于 CXCL12 低组。此外，CXCL12 高难治性血细胞减少伴多系发育异常（RCMD）病例比 CXCL12 低 RCMD 病例更倾向于进展为难治性贫血伴原始细胞增多（RAEBs）或 AML-MRC。这些结果表明，CXCL12(+)细胞构成了 CD34(+)造血细胞的龛，可能与 CD34(+)造血细胞的存活/抗凋亡和 MDS 的疾病进展有关。因此，CXCL12(+)细胞可能代表 MDS 的一个新的治疗靶点。
