Haploinsufficiency of NR3C1 drives glucocorticoid resistance in adult acute lymphoblastic leukemia cells by down-regulating the mitochondrial apoptosis axis, and is sensitive to Bcl-2 blockage
Relapse represents the leading cause of death in both child and adult patients with acute lymphoblastic leukemia (ALL). Development of chemo-resistance is ultimately responsible for treatment failure and relapse, therefore understanding the molecular basis underlying resistance is imperative for dev...
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Published in | Cancer cell international Vol. 19; no. 1; p. 218 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
BioMed Central
23.08.2019
BMC |
Subjects | |
Online Access | Get full text |
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Summary: | Relapse represents the leading cause of death in both child and adult patients with acute lymphoblastic leukemia (ALL). Development of chemo-resistance is ultimately responsible for treatment failure and relapse, therefore understanding the molecular basis underlying resistance is imperative for developing innovative treatment strategies. Glucocorticoids (GCs) such dexamethasone and prednisolone are the backbone of combination chemotherapy regimens for treating all lymphoid tumors. However, the biological mechanisms of primary GC resistance in ALL is not completely understood. We previously performed a longitudinal whole-exome sequencing analysis on diagnosis/relapse pairs from adult patients with ALL. Our data revealed that relapse-specific truncation mutations in the
gene, encoding the GC receptor, are frequently detected.
In the current study, we used discovery-based strategies including RNA sequencing (RNA-seq) and CRISPR/Cas9, followed by confirmatory testing, in human ALL cell lines, bone marrow blast samples from ALL patients and xenograft models, to elucidate the mechanisms responsible for resistance.
Our results revealed a positive correlation between endogenous expression of
in ALL cells and sensitivity to GCs and clinical outcomes. We further confirmed that ectopic expression of
in ALL cells could reverse GC resistance, while deletion of
confers resistance to GCs in ALL cell lines and xenograft models. RNA-seq analysis revealed a remarkable abundance of gene signatures involved in pathways in cancer, DNA replication, mismatch repair, P53 signalling, cell cycle, and apoptosis regulated by
Significantly increased expression of pro-apoptotic genes including
,
,
,
and
, and decreased transcription of anti-apoptotic genes including
,
and
were observed in GC-resistant ALL cells following ectopic expression of
. Finally, we explored that GC resistance in ALL cells with haploinsufficiency of
can be treated with Bcl-2 blockage.
Our findings suggest that the status of
gene mutations and basal expression levels of
in ALL cells are associated with sensitivity to GCs and clinical treatment outcomes. Early intervention strategies by rational combination of Bcl-2 blockage may constitute a promising new treatment option to GC-resistant ALL and significantly improving the chances of treating poor prednisone responders. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1475-2867 1475-2867 |
DOI: | 10.1186/s12935-019-0940-9 |