Unconventional function of the glycolytic enzyme HK3 in AML cell death Group Tschan We identified non-glycolytic, pro-survival functions of hexokinase HK3 in AML cells. Elevated HK3 mRNA levels are associated with myeloid oncogenes such as MLL/KMT2A rearrangements, and correlate with poor survival. Notably, high HK3 levels are linked to reduced initial responsiveness and secondary resistance to the BCL2 antagonist venetoclax. We propose that HK3 supports AML survival and dampens therapy responses through non-metabolic functions involving BCL2 family interactions and subcellular localization. Nuclear localization of HK3 in myeloid cells and expression in macrophages of the colon
Novel autophagy subtype associated with ATRA-therapy of APL cells Group Tschan Although acute promyelocytic leukemia (APL) is effectively treated with all-trans retinoic acid (ATRA) and chemotherapy, other AML subtypes do not benefit from this differentiation therapy. Our data highlight the critical role of non-canonical autophagy during ATRA-therapy. We found significantly reduced expression of the non-canonical autophagy gene ATG16L2, but not the canonical ATG16L1, in APL. In line, depleting ATG16L2 attenuated differentiation. We propose that ATRA-induced APL differentiation requires selective cargo degradation via an ATG16L1-independent mechanism. Transmission electron microscopy of NB4 APL cells upon ATRA treatment
Function and post-translational regulation of the oncogenic splice variant DMTF1 Group Tschan We found that knocking down the oncogenic DMTF1β isoform reduces migration and invasion of prostate and breast cancer cells. Interestingly, this was accompanied by the downregulation of autophagy-related pathways and autophagic flux. Mechanistically, we identified the autophagy protein ULK1 as a novel interaction partner of DMTF1β, whereby DMTF1β promoted ULK1 protein stability. Additionally, we discovered that DMTF1β is a short-lived protein that undergoes polyubiquitination in a β-domain-specific manner, leading to proteasomal degradation. β-specific domain DTMF1β is associated with poly-ubiquitination
