SPINK2 silencing suppresses leukemic proliferation and restores myeloid commitment via MECOM downregulation in acute myeloid leukaemia

Currently, no effective options are available for the treatment of those patients, and the discovery of novel therapeutic strategies represent an urgent clinical priority. We previously developed a bioinformatic framework for the identification of novel molecular vulnerabilities for disease stratification and treatment and observed SPINK2, a serine protease inhibitor Kazal-type 2, as a novel and promising candidate target in AML, with particularly pronounced effect in complex karyotype patients.

Using publicly available bulk and single cell RNA-seq datasets, we discovered a robust association between SPINK2 and cell cycle regulators, most notably S-phase genes. By performing shRNA-mediated genetic manipulation of SPINK2 expression in a complex karyotype AML cell lines, we marked a profound impairment of proliferation coupled with an induction of terminal myeloid commitment. Moreover, SPINK2-deficient FUJIOKA cells revealed a significant correlation between SPINK2 and MECOM expression, consistent with findings in patients harbouring complex karyotypes, yet absent in other AML subsets from the TARGET-AML cohort.