Abstract
BackgroundAcute lymphoblastic leukemia (ALL) cells treated with drugs can become drug-tolerant if co-cultured with protective stromal mouse embryonic fibroblasts (MEFs).ResultsWe performed transcriptional profiling on these stromal fibroblasts to investigate if they were affected by the presence of drug-treated ALL cells. These mitotically inactivated MEFs showed few changes in gene expression, but a family of sequences of which transcription is significantly increased was identified. A sequence related to this family, which we named cassini, was selected for further characterization. We found that cassini was highly upregulated in drug-treated ALL cells. Analysis of RNAs from different normal mouse tissues showed that cassini expression is highest in spleen and thymus, and can be further enhanced in these organs by exposure of mice to bacterial endotoxin. Heat shock, but not other types of stress, significantly induced the transcription of this locus in ALL cells. Transient overexpression of cassini in human 293 embryonic kidney cells did not increase the cytotoxic or cytostatic effects of chemotherapeutic drugs but provided some protection. Database searches revealed that sequences highly homologous to cassini are present in rodents, apicomplexans, flatworms and primates, indicating that they are conserved in evolution. Moreover, CASSINI RNA was induced in human ALL cells treated with vincristine. Surprisingly, cassini belongs to the previously reported murine family of γ-satellite/major satellite DNA sequences, which were not known to be present in other species.ConclusionsOur results show that the transcription of at least one member of these sequences is regulated, suggesting that this has a function in normal and transformed immune cells. Expression of these sequences may protect cells when they are exposed to specific stress stimuli.
Highlights
Acute lymphoblastic leukemia (ALL) cells treated with drugs can become drug-tolerant if co-cultured with protective stromal mouse embryonic fibroblasts (MEFs)
Microarray analysis was performed on RNA isolated from MEFs exposed to DMSO, to nilotinib, and to nilotinib plus ALL cells at the end of the treatment on day 9 when the ALL cells had recovered (Figure 1A, B)
Compared to DMSO-treated MEFs, only 59 probesets reported larger than 2-fold increased expression in MEFs exposed to nilotinibtreated ALL cells
Summary
Acute lymphoblastic leukemia (ALL) cells treated with drugs can become drug-tolerant if co-cultured with protective stromal mouse embryonic fibroblasts (MEFs). The bone marrow microenvironment provides protection to acute lymphoblastic leukemia (ALL) cells against drug treatment and is a frequent site of leukemia relapse. Some of the factors produced by stromal cells that provide protection to the ALL cells have been identified, and include stromally produced SDF1α [4,9,10]. It is unclear if the presence of drug-treated ALL cells affects the stromal fibroblasts. These experiments led to the identification of an evolutionarily conserved family of multi-copy sequences, of which transcription is increased in both the ALL cells and the irradiated stromal cells when ALL cells are subjected to drug treatment
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