Abstract
BackgroundIn addition to genetic and epigenetic alteration, post-translational modification of proteins plays a critical role in the initiation, progression and maturation of acute myeloid leukemia (AML).MethodsThe SUMOylation site of sPRDM16 at K568 was mutated to arginine by site-directed mutagenesis. THP-1 acute myeloid leukemia cells were transduced with a lentivirus containing wild type or K568 mutant sPRDM16. Proliferation, self-renewal and differentiation of transduced THP-1 cells were analyzed both in vitro cell culture and in mouse xenografts. Gene expression profiles were analyzed by RNA-seq.ResultsOverexpression of sPRDM16 promoted proliferation, enhanced self-renewal capacity, but inhibited differentiation of THP-1 acute myeloid leukemia cells. We further confirmed that K568 is a bona fide SUMOylation site on sPRDM16. Mutation of the sPRDM16 SUMOylation site at K568 partially abolished the capacity of sPRDM16 to promote proliferation and inhibit differentiation of acute myeloid leukemia cells both in vitro and in mouse xenografts. Furthermore, THP-1 cells overexpressing sPRDM16-K568R mutant exhibited a distinct gene expression profile from wild type sPRDM16 following incubation with PMA.ConclusionsOur results suggest that K568 SUMOylation of sPRDM16 plays an important role in the progression of acute myeloid leukemia.
Highlights
In addition to genetic and epigenetic alteration, post-translational modification of proteins plays a critical role in the initiation, progression and maturation of acute myeloid leukemia (AML)
SPRDM16 SUMOylation was decreased in sPRDM16-WTTHP-1 cells after incubation with PMA (Fig. 3g). These results suggest that mutation of sPRDM16 SUMOylation site at K568 reduced the capacity of sPRDM16 to induce proliferation and inhibit differentiation of AML cells, suggesting that K568 SUMOylation of sPRDM16 played an important role in the pathogenesis of AML
The difference was not statistically significant. These results indicate that sPRDM16 SUMOylation enhanced engraftment of systemic THP-1 transplantation leukemia in NOD.CB17-Prkdcscid/J (NOD/SCID) mice, suggesting that mutation of sPRDM16 K568R partially attenuates the progression of AML in vivo
Summary
In addition to genetic and epigenetic alteration, post-translational modification of proteins plays a critical role in the initiation, progression and maturation of acute myeloid leukemia (AML). Leukemia results from the accumulation of genetic and epigenetic alterations during the multistep process of tumorigenesis, including activation of oncogenes and/or inactivation of tumor suppressor genes. Within the past decade evidence that post-translational modification of proteins, including phosphorylation [2], acetylation [3], ubiquitination [4] and SUMOylation [5, 6], plays a critical role in the initiation, progression and maturation of AML has accumulated. SUMOylation alters the localization, activity or stability of target proteins [19], and is reversed by a family of Sentrin/SUMO-specific proteases (SENPs)
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