title: CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes.
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.
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Abe-Suzuki
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Morito
authors.initials: M
authors.lastname: Kurata
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Abe
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Iichiroh
authors.initials: I
authors.lastname: Onishi
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kirimura
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Manami
authors.initials: M
authors.lastname: Nashimoto
authors.affiliation: Department of Pathology, National Hospital Organization, Kumamoto Medical Center, Kumamoto, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Murayama
authors.affiliation: Department of Internal Medicine, National Hospital Organization, Kumamoto Medical Center, Kumamoto, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hidaka
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kitagawa
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018450:Disease Progression; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019253:Proto-Oncogene Proteins c-bcl-2