Only some acute lymphoblastic leukemia (ALL) cells are thought to be capable of proliferating to maintain the leukemic clone, and these cells may be the most relevant to target with treatment regimens. We have developed a serum-free suspension culture (SC) system that supported growth of B-ALL cells from 33 patients for up to 6 weeks. ALL cells from 28 cases (85%) were expanded in this system, and growth was superior in SC than in long-term bone marrow culture.
Key Points
IL-15 has been implicated in CNS disease and leukemogenesis, but the biological mechanisms are unknown. IL-15 increases pre-B ALL growth and upregulates CNS homing molecules, and MEK/ERK, PI3K, and NF-κB inhibitors block IL-15 growth effects.
Key Points• First report demonstrating in vivo elimination of multiple LIC populations from childhood ALL cases using animal models.• In vivo models of leukemia are essential for drug evaluation studies.
Summary. The mechanism of action of anti-thymocyte globulin (ATG) in aplastic anaemia (AA) is complex. Bone marrow (BM) CD34 1 cells in AA have been shown to be more apoptotic and have a higher expression of Fas antigen (Fas-ag) than in normal donors. The aims of this study were to delineate further the mechanism for increased bone marrow progenitor cell apoptosis in AA and investigate the effects of ATG on apoptosis and Fas-ag expression. BM was obtained from six normal donors and 10 untreated AA patients. We confirmed that AA BM CD34 1 cells were more apoptotic than normal donor cells (P 0´002). Following treatment with ATG, the mean percentage reduction of apoptosis was 34% (9´2±65´9%). BM from 30 AA and 10 normal donors was then stained for CD34, Fas-ag and 7-AminoActinomycin D. The proportion of CD34 1 Fas 1 cells was higher in untreated AA (P 0´0001) than in normal donors. Results also showed that the majority of CD34 1 Fas 1 cells were apoptotic/dead in normal donors (mean 81%) and AA (88%), indicating that Fas is involved in apoptosis of CD34 1 cells. In contrast, the majority of CD34 1 Fas 2 cells in normal donors were live (mean 91%), while two patterns emerged in untreated AA. In seven patients, the majority of cells were live, however, in the remaining eight patients, the majority of cells were apoptotic/dead, suggesting an alternative mechanism for apoptosis in addition to Fas-ag. Finally, we have shown that in vivo ATG treatment reduced the expression of Fas-ag on AA BM CD34 1 cells.
Hematopoietic stem/progenitor cells (HSPCs) reside in specialized bone marrow microenvironmental niches, with vascular elements (endothelial/mesenchymal stromal cells) and CXCR4‐CXCL12 interactions playing particularly important roles for HSPC entry, retention, and maintenance. The functional effects of CXCL12 are dependent on its local concentration and rely on complex HSPC‐niche interactions. Two Junctional Adhesion Molecule family proteins, Junctional Adhesion Molecule‐B (JAM)‐B and JAM‐C, are reported to mediate HSPC‐stromal cell interactions, which in turn regulate CXCL12 production by mesenchymal stromal cells (MSCs). Here, we demonstrate that another JAM family member, JAM‐A, is most highly expressed on human hematopoietic stem cells with in vivo repopulating activity (p < .01 for JAM‐Ahigh compared to JAM‐AInt or Low cord blood CD34+ cells). JAM‐A blockade, silencing, and overexpression show that JAM‐A contributes significantly (p < .05) to the adhesion of human HSPCs to IL‐1β activated human bone marrow sinusoidal endothelium. Further studies highlight a novel association of JAM‐A with CXCR4, with these molecules moving to the leading edge of the cell upon presentation with CXCL12 (p < .05 compared to no CXCL12). Therefore, we hypothesize that JAM family members differentially regulate CXCR4 function and CXCL12 secretion in the bone marrow niche. Stem Cells 2016;34:1664–1678
The mechanism of action of anti-thymocyte globulin (ATG) in aplastic anaemia (AA) is complex. Bone marrow (BM) CD34(+) cells in AA have been shown to be more apoptotic and have a higher expression of Fas antigen (Fas-ag) than in normal donors. The aims of this study were to delineate further the mechanism for increased bone marrow progenitor cell apoptosis in AA and investigate the effects of ATG on apoptosis and Fas-ag expression. BM was obtained from six normal donors and 10 untreated AA patients. We confirmed that AA BM CD34(+) cells were more apoptotic than normal donor cells (P = 0.002). Following treatment with ATG, the mean percentage reduction of apoptosis was 34% (9.2-65.9%). BM from 30 AA and 10 normal donors was then stained for CD34, Fas-ag and 7-AminoActinomycin D. The proportion of CD34(+) Fas(+) cells was higher in untreated AA (P = 0.0001) than in normal donors. Results also showed that the majority of CD34(+) Fas(+) cells were apoptotic/dead in normal donors (mean 81%) and AA (88%), indicating that Fas is involved in apoptosis of CD34(+) cells. In contrast, the majority of CD34(+) Fas(-) cells in normal donors were live (mean 91%), while two patterns emerged in untreated AA. In seven patients, the majority of cells were live, however, in the remaining eight patients, the majority of cells were apoptotic/dead, suggesting an alternative mechanism for apoptosis in addition to Fas-ag. Finally, we have shown that in vivo ATG treatment reduced the expression of Fas-ag on AA BM CD34(+) cells.
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