The anaphase-promoting complex (APC/C) ubiquitin ligase is the target of the spindle-assembly checkpoint (SAC), ubiquitylating protein substrates whose degradation regulates progress through mitosis1-3. The identity of the ubiquitin-conjugating (E2) enzymes that work with the APC/C is unclear. In an RNA interference screen for factors that modify release from drug-induced SAC activation, we identify here the E2 enzyme, UBE2S, as an auxillary factor for the APC/C that promotes mitotic exit. UBE2S is dispensable in a normal mitosis, but its depletion prolongs drug-induced mitotic arrest and suppresses mitotic slippage. In vitro, UBE2S elongates ubiquitin chains initiated by the E2 enzymes UBCH10 and UBCH5, enhancing the degradation of APC/C substrates by the proteasome. Indeed, following release from SAC arrest, UBE2S-depleted cells neither degrade crucial APC/C substrates, nor silence this checkpoint, whereas SAC bypass via BUBR1 depletion or Aurora-B inhibition negates the requirement for UBE2S. Thus, UBE2S acts with the APC/C in a two-step mechanism controlling substrate ubiquitylation that is essential for mitotic exit after prolonged SAC activation, providing a new model for APC/C function in human cells.
Minimal residual disease (MRD) is associated with adverse outcome in AML after myeloablative (MA) hematopoietic cell transplantation (HCT). We compared this association with that seen after nonmyeloablative (NMA) conditioning in 241 adults receiving NMA (n=86) or MA (n=155) HCT for AML in first remission with pre-HCT bone marrow aspirates assessed by flow cytometry. NMA patients were older and had more comorbidities and secondary leukemias. Three-year relapse estimates were 28% and 57% for MRDneg and MRDpos NMA patients, and 22% and 63% for MA patients. Three-year overall survival (OS) estimates were 48% and 41% for MRDneg and MRDpos NMA patients and 76% and 25% for MA patients. This similar OS after NMA conditioning was largely accounted for by higher non-relapse mortality (NRM) in MRDneg (30%) compared to MRDpos (10%) patients, whereas the reverse was found for MRDneg (7%) and MRDpos (23%) MA patients. A statistically significant difference between MA and NMA patients in the association of MRD with OS (P<0.001) and NRM (P=0.002) but not relapse (P=0.17) was confirmed. After adjustment, the risk of relapse was 4.51-times (P<0.001) higher for MRDpos patients. These data indicate that the negative impact of MRD on relapse risk is similar after NMA and MA conditioning.
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