Modulating Schlafen 12 Activity Using Velcrins in Acute Myeloid Leukemia Cells

Schlafen 12 (SLFN12) belongs to the Schlafen (SLFN) family of proteins, classified as

interferon-stimulated genes with diverse biological functions. In humans, SLFNs exert a role via

their endonuclease and/or helicase domains in cellular proliferation, differentiation, immune

responses, and chemosensitivity of malignant cells. Accumulating evidence suggests that SLFN

family members could serve as prognostic markers in certain malignancies and may be

potential novel therapeutic targets. Using data from the TCGA database, we found that SLFN12

is notably overexpressed in acute myeloid leukemia (AML). To modulate SLFN12 activity in

AML cell lines, we utilized velcrins. Velcrins are a class of molecular glues that facilitate

heterotetramer formation between SLFN12 and phosphodiesterase 3A (PDE3A). This stabilizes

SLFN12 protein and enhances its RNAse activity, ultimately inducing cancer cell death. Velcrins

effectively reduced cell viability and leukemic progenitor potential in colony forming assays in

AML cell lines, with particular sensitivity observed in HEL cells characterized by elevated

SLFN12 and PDE3A levels. Further investigation revealed that velcrin treatment promoted the

SLFN12-PDE3A interaction and potently induced apoptosis in AML cell lines. In cell lines with

lower PDE3A levels, PDE3B, an isoform of PDE3, seems to be partially mediating velcrin

sensitivity as co-immunoprecipitation analysis confirmed a PDE3B-SLFN12 protein interaction

following velcrin treatment in U937 cells, which do not express PDE3A. Moreover, in vivo

experiments utilizing HEL subcutaneous xenografts, demonstrated significant reduction in tumor

burden and prolonged survival upon velcrin treatment, further supporting its therapeutic efficacy

in AML. We also demonstrated enhanced effects in vitro when combined with azacitidine in the

reduction of leukemic cell viability. Altogether, these findings demonstrate an important role for

SLFN12 in AML and raise the potential of velcrins as agents with unique activity in the

treatment of AML.

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