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Transplantation of in vitro-manipulated cells is widely used in hematology. While transplantation is well recognized to impose severe stress on transplanted cells, the nature of transplant-induced stress remains elusive. Here, we propose that the lack of amino acids in serum is the major cause of transplant-induced stress. Mechanistically, amino acid deficiency decreases protein synthesis and nutrient consummation. However, in cells with overactive AKT and ERK, mTORC1 is not inhibited and protein synthesis remains relatively high. This impaired signaling causes nutrient depletion, cell cycle block, and eventually autophagy and cell death, which can be inhibited by cycloheximide or mTORC1 inhibitors. Thus, mTORC1-mediated amino acid signaling is critical in cell fate determination under transplant-induced stress, and protein synthesis inhibition can improve transplantation efficiency.

CD19-chimeric antigen receptor (CAR)-based T-cell therapy has produced promising clinical responses in patients with relapsed or refractory B-cell malignancies. However, a significant portion of patients with mature B cell-derived malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), do not respond to CD19-CAR-T cell therapy. Whether any characteristics and biomarkers intrinsic to cancer cells themselves can predict the CD19-CAR-T cell therapeutic response remains largely unknown. Surprisingly, by using experimental models, we show here that malignant B cells bearing CD21, a mature B cell marker, could not be efficiently killed by CD19-CAR-T cells. CD19, CD21, and CD81, together with CD225, form the B cell coreceptor complex that enhances B cell-mediated signaling. Our results indicated that CD21 affected the recognition of CD19-positive tumor cells by CD19-CAR-T cells and impaired the antitumor capacities of these effector cells. We have not only uncovered a mechanism underlying the impairment of CD19-CAR-T cells in mature B cell-derived CLL and NHL, but also proposed a pretreatment biomarker that may predict CD19-CAR-T cell therapeutic response, thus preventing foreseeable therapy failure and suggesting optimal personized therapies.

Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug‐tolerant cancer cells, which offer therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively, however the ways by which drug‐tolerant cancer cells orchestrate their adaptive responses to drug challenges remain largely unknown. Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed‐lineage leukemia (MLL) cells. This adaptive process involved reversible downregulation of cyclin A1, which promoted PI resistance through cell‐cycle arrest. PI‐tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL‐mediated histone H3 lysine 4 methylation. These results reveal the importance of cyclin A1‐engaged cell‐cycle regulation in PI resistance in MLL cells, and suggest that cell‐cycle re‐entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance., Cyclin A1 suppression elicits the development of transient proteasome inhibitor (PI) tolerance in mixed‐lineage leukemia cells. Reduction of MLL and cyclin A1 is associated with patient relapse and reduced survival in acute lymphoblastic leukemia. Combined PI with deubiquitinating enzyme (DUB) inhibitors overcomes drug resistance by restoring cyclin A1 expression through chromatin crosstalk. Cell‐cycle re‐entry by DUB inhibitors represents a potential therapeutic strategy to prevent acquired drug resistance.