Acute myeloid leukaemia with t(8;21)(q22;q22.3) and loss of the X chromosome.
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ABSTRACT:
SUBMITTER: Mohamed M
PROVIDER: S-EPMC4533636 | biostudies-other | 2015 Aug
REPOSITORIES: biostudies-other
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Project description:A hallmark of acute myeloid leukaemias (AMLs) are chromosomal rearrangements that give rise to novel leukaemia-specific fusion genes. Most of these fusion genes are both initiating and driving events in AML and therefore constitute ideal therapeutic targets but are challenging to target by conventional drug development. siRNAs are frequently used for the specific suppression of fusion gene expression but require special formulations for efficient in vivo delivery. Here we describe the use of siRNA-loaded lipid nanoparticles for the specific therapeutic targeting of the leukaemic fusion gene RUNX1/ETO. Transient knockdown of RUNX1/ETO reduces its binding to its target genes and alters the binding of RUNX1 and its co-factor CBFβ. Transcriptomic changes in vivo were associated with substantially increased median survival of a t(8;21)-AML mouse model. Importantly, transient knockdown in vivo causes long-lasting inhibition of leukaemic proliferation and clonogenicity, induction of myeloid differentiation and a markedly impaired re-engraftment potential in vivo. These data strongly suggest that temporary inhibition of RUNX1/ETO results in long-term restriction of leukaemic self-renewal. Our results provide proof for the feasibility of targeting RUNX1/ETO in a pre-clinical setting and support the further development of siRNA-LNPs for the treatment of fusion gene-driven malignancies.
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Project description:Acute myeloid leukemia (AML) is a major blood cancer with poor prognosis. New therapies are needed to target oncogene-driven leukemia stem cells, which account for relapse and resistance. Chromosome translocation t(8;21), which produces RUNX1-ETO (R-E) fusion oncoprotein, is found in ~13% AML. R-E dominance negatively inhibits global gene expression regulated by RUNX1, a master transcription factor for hematopoiesis, causing increased self-renewal and blocked cell differentiation of hematopoietic progenitor cells, and eventually leukemia initiation. Methods: Connectivity-Map followed by biological activity testing were used to identify candidate compounds that can inhibit R-E-mediated gene transcription. Molecular mechanistic studies were also performed. Results: Glucocorticoid drugs, such as betamethasone and dexamethasone, were found to exhibit potent and selective in vitro and in vivo activities against R-E leukemia, as well as strong synergy when combined with chemotherapeutics. Microarray analysis showed that treatment with glucocorticoids significantly inhibited R-E's activity and reactivated that of RUNX1. Such gene expression changes caused differentiation and apoptosis of R-E leukemia cells. Our studies also show a possible molecular mechanism for the targeted therapy. Upon treatment with a glucocorticoid drug, more glucocorticoid receptor (GR) was translocated into the nucleus and bound to DNA, including promoters of RUNX1 target genes. GR was found to associate with RUNX1, but not R-E. This interaction increased binding of RUNX1 to DNA and reduced that of R-E, shifting to a RUNX1 dominance. Conclusion: Glucocorticoid drugs represent a targeted therapy for AML with chromosome translocation t(8:21). Given their high activity, favorable human pharmacokinetics as well as synergy with chemotherapeutics, glucocorticoids could be clinically useful to treat R-E AML.
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