Chikako Satoh

Identification and Hematopoietic Potential of CD45− Clonal Cells with Very Immature Phenotype (CD45−CD34−CD38−Lin−) in Patients with Myelodysplastic Syndromes

CD45 is a hematopoietic lineage‐restricted antigen that is expressed on all hematopoietic cells except for some mature cell types. Cells expressing CD45 and CD34 but lacking CD38 and lineage antigens (CD45+CD34+CD38−Lin− cells) are well‐documented hematopoietic stem cells (HSCs), and CD45+CD34−CD38−Lin− cells are probably less mature HSCs. In myelodysplastic syndromes (MDS), the malignant transformation site is a matter of debate, and CD45+CD34+CD38−Lin− HSCs were recently reported to be clonal. In the study reported here, we detected CD45−CD34−CD38−Lin− cells in the peripheral blood and bone marrow of patients with MDS and isolated them by successive application of density centrifugation, magnetic cell sorting, and fluorescence‐activated cell sorting. Fluorescence in situ hybridization showed that CD45−CD34−CD38−Lin− cells had the same chromosomal aberration as the myeloblasts. In addition to CD45− and CD34−, they lacked CD117 and CD133 expression. Generally, MDS cells have extremely reduced hematopoietic potential compared with normal hematopoietic cells, but we documented the following in some patients. Freshly isolated CD45−CD34−CD38−Lin− cells did not form any hematopoietic colonies but had long‐term culture‐initiating cell activity. When cocultured with stroma cells, CD45−CD34−CD38−Lin− cells showed only weak potential for proliferation and differentiation, yet they differentiated into CD34+ cells and then mature myeloid cells. This newly identified cell population represents the most immature immunophenotype so far identified in the hematopoietic lineage and is involved in the malignant clone in MDS.

Functional B7.2 and B7-H2 Molecules on Myeloma Cells Are Associated with a Growth Advantage

Purpose: B7 family molecules expressed on antigen-presenting cells stimulate or inhibit normal immune responses. The aim of this study was to investigate whether functional B7.2 and B7-H2 molecules are expressed on myeloma cells and, if so, whether they are associated with pathophysiology in myeloma. Experimental Design: The expression of B7.2 and B7-H2 molecules on normal plasma and neoplastic (myeloma) plasma cells was analyzed. The cell proliferation and immunomodulatory function of myeloma cells related to B7.2 and B7-H2 expression were examined. Results: Human myeloma cell lines commonly expressed B7.2 and B7-H2 molecules. B7.2 expression on plasma cells was more common in myeloma patients (n = 35) compared with that in patients with monoclonal gammopathy of unknown significance (n = 12) or hematologically normal individuals (n = 10). Plasma cells expressing B7-H2 were observed in myeloma patients alone, although rarely. Patients whose myeloma cells showed high B7.2 expression were more anemic and thrombocytopenic than other myeloma patients. The expression of these molecules was induced or augmented by cultivating myeloma cells with autologous stroma cells or tumor necrosis factor-α, a key cytokine in myeloma biology. Cell proliferation was more rapid in the B7.2+ and B7-H2+ populations compared with the B7.2− and B7-H2− populations, respectively, in the human myeloma cell lines examined. B7.2 and B7-H2 molecules on myeloma cells induced normal CD4+ T cells to proliferate and produce soluble factors, including interleukin-10 that stimulate myeloma cell proliferation. Conclusions: Functional B7.2 and B7-H2 molecules detected on myeloma cells may be involved in the pathophysiology of myeloma.

Aggressive characteristics of myeloblasts expressing CD7 in myelodysplastic syndromes.

Clinical data suggest that CD7+ myeloblasts are linked with poor prognosis in myeloid malignancies including myelodysplastic syndromes (MDS). To explore the biology behind this, we compared cell characteristics between CD34+CD7+ and CD34+CD7- myeloblasts from an MDS cell line and fresh samples from MDS patients. Compared with CD34+CD7- myeloblasts, CD34+CD7+ myeloblasts showed greater proliferative capacity, more active cell cycling, and less apoptosis. In analyses of a cell line, CD34+CD7+ myeloblasts produced CD34+CD7- myeloblasts and showed lower expressions of interleukin-8 and chemokine (C-C motif) ligand 2 genes, suggesting immaturity of these cells. These findings might underlie the clinical aggressiveness in CD7+ MDS.