Normal T cell development depends upon interaction between progenitor cells and the thymic microenvironment. However, the ultimate T cell precursors derive from haematopoietic progenitors in the bone marrow (BM). The malignant counterpart of immature T cells, namely T acute lymphoblastic leukaemia (T-ALL) cells, arise inside the thymus and almost always spread to BM early in the clinical course. Thus, BM and thymic stromal microenvironments play a crucial role in the development of normal and neoplastic immature T cells. In this work we investigated whether the spontaneous apoptosis observed in vitro in normal and neoplastic immature T cells could be regulated by the interaction with BM- and/or thymus-derived stromal cells. To address this issue, we performed lympho-stromal co-cultures between normal human BM stromal or thymic epithelial (TE) cells and normal human unfractionated thymocytes or blasts derived from 5 adult T-ALL patients. The spontaneous apoptosis was completely abolished when normal or leukaemic T cells were co-cultured with BM-derived stromal cells whereas the interaction with TE cells was ineffective. Furthermore, rescued leukaemic -but not normal- T cells were induced to proliferate by the interaction with BM stromal cells. When BM stroma was replaced with established cell lines used as controls, no protective or proliferative effects were observed. Both cell protection and proliferation were dependent upon cell-cell adhesion, as BM-derived supernatant was unable to rescue or induce proliferation in immature T cells. These results point out the role of BM stroma in the regulation of immature T cell survival. On the opposite side, they highlight the preserved ability of T cell precursors to respond to survival stimuli from BM microenvironment. This mechanism, strengthened by the proliferative potential of T blasts, could play a role in the blast spreading to BM during pathogenesis of T-ALL.

Bone marrow-, but not thymus-, derived stromal cells inhibit spontaneous apoptosis and induce proliferation in blasts of T-lineage ALL

SCUPOLI, Maria;VINANTE, Fabrizio;SANTINI, Francesco;PIZZOLO, Giovanni
2001

Abstract

Normal T cell development depends upon interaction between progenitor cells and the thymic microenvironment. However, the ultimate T cell precursors derive from haematopoietic progenitors in the bone marrow (BM). The malignant counterpart of immature T cells, namely T acute lymphoblastic leukaemia (T-ALL) cells, arise inside the thymus and almost always spread to BM early in the clinical course. Thus, BM and thymic stromal microenvironments play a crucial role in the development of normal and neoplastic immature T cells. In this work we investigated whether the spontaneous apoptosis observed in vitro in normal and neoplastic immature T cells could be regulated by the interaction with BM- and/or thymus-derived stromal cells. To address this issue, we performed lympho-stromal co-cultures between normal human BM stromal or thymic epithelial (TE) cells and normal human unfractionated thymocytes or blasts derived from 5 adult T-ALL patients. The spontaneous apoptosis was completely abolished when normal or leukaemic T cells were co-cultured with BM-derived stromal cells whereas the interaction with TE cells was ineffective. Furthermore, rescued leukaemic -but not normal- T cells were induced to proliferate by the interaction with BM stromal cells. When BM stroma was replaced with established cell lines used as controls, no protective or proliferative effects were observed. Both cell protection and proliferation were dependent upon cell-cell adhesion, as BM-derived supernatant was unable to rescue or induce proliferation in immature T cells. These results point out the role of BM stroma in the regulation of immature T cell survival. On the opposite side, they highlight the preserved ability of T cell precursors to respond to survival stimuli from BM microenvironment. This mechanism, strengthened by the proliferative potential of T blasts, could play a role in the blast spreading to BM during pathogenesis of T-ALL.
Acute leukemia, microenvironment, cell survival
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/472549
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