CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes.
Lab Invest
; 94(11): 1212-23, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25199050
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Medula Óssea
/
Síndromes Mielodisplásicas
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Células-Tronco Hematopoéticas
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Leucemia Mieloide Aguda
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Quimiocina CXCL12
Tipo de estudo:
Observational_studies
/
Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article