Session 5: Proteostatic-stress in leukemia
National University of Ireland, Galway, Ireland
Malignant cells are protected from the damaging effect of mutant proteins, altered organelle - and cellular functions by cellular stress pathways. These pathways can maintain viability and fuel drug resistance by upregulating pro-survival and/or anti-apoptotic proteins. As a trade off however, the buffering capacity of these pathways is often exhausted in tumour cells making them highly sensitive to additional stresses.
The proteostatic network is one such example. Multiple myeloma cells and AML cells have been found to depend on the ubiquitin proteasome system offering potential targets for therapy. In the present project we have investigated the effect of the NEDD8 activating enzyme (NAE) inhibitor, pevonedistat (MLN4924) in acute myeloid leukemia (AML). NEDD8 is a ubiquitin-like protein. NEDD8, after being activated by NAE can be conjugated to cullin-RING ligases (CRLs), one of the three classes of ubiquitin E3 ligases, involved in degradative protein ubiquitination. NEDDylation of CRLs switches on their E3 ligase activity. We found that inhibition of CRL function with pevonedistat in AML cells induced a circuitry of CEBPalpha and p53 induction and activation, driving BH3-only Bcl-2 protein induction culminating in Noxa-dependent apoptosis.
Interestingly, while we found that bone marrow stromal cells protected AML cells from a broad range of drugs, including genotoxic drugs (cytarabine, daunorubicin) as well as tyrosine kinase inhibitors (sorafenib, quizartinib) via secreted factors, they failed to give protection against pevonedistat. In the stromal cells pevonedistat activated p53 and induced p21 but did not induce cell death. Pevonedistat also interfered with the secretion of cytokines and chemokines that drive AML drug resistance.
Overall, stressors causing proteostatic-imbalance may have the potential to disrupt the paracrine communication between the leukemic cells and the bone marrow microenvironment resulting in increased drug sensitivity.