T-complex protein 1 (TCP1) is one of the subunits of chaperonin-containing T complex (CCT), which is involved in protein folding, cell proliferation, apoptosis, cell cycle regulation, and drug resistance. Investigations have demonstrated that TCP1 is a factor being responsible for drug resistance in breast and ovarian cancer. However, the TCP1 role in acute myeloid leukemia (AML) remains elusive. In the present study, we discovered that the TCP1 expression was elevated in AML patients and high TCP1 expression was associated with low complete response rate along with poor overall survival. TCP1 showed higher expression in the adriamycin-resistant leukemia cell line HL60/A and K562/A, comparing to their respective parent cells HL60 and K562 cells. TCP1 inhibition suppressed drug resistance in HL60/A and K562/A cells, whereas TCP1 overexpression in HL60 cells incremented drug resistance, both in vitro and in vivo. Mechanistic investigations revealed that TCP1 inhibited autophagy and adriamycin-induced cell apoptosis, and TCP1-mediated autophagy inhibition conferred resistance to adriamycin-induced cell apoptosis. Furthermore, TCP1 interacted with AKT and mTOR to activate AKT/mTOR signaling, which negatively regulates apoptosis and autophagy. Pharmacological inhibition of AKT/mTOR signal particularly activated autophagy and resensitized TCP1-overexpressing HL60 cells to adriamycin. These findings identify a novel role of TCP1 regarding drug resistance in AML, which advise a new strategy for overcoming drug resistance in AML through targeting TCP1/AKT/mTOR signaling pathway.

Objectives: To compare the outcomes of tyrosine kinase inhibitors (TKIs) in combination with reduced-dose chemotherapy with those of standard induction chemotherapy, as well as the outcomes between chemotherapy and transplantation, in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Methods: We retrospectively reviewed cases of Ph+ ALL treated with TKIs and combination chemotherapy. The patients were allocated to either the TKIs with reduced-dose chemotherapy group or the TKIs with standard chemotherapy group. In additions, patients were further stratified into either the transplant group or the non-transplant group. Results: The complete remission rate (88.7% vs. 83.9%, p = 0.372), major molecular response (58.9% vs. 56.0%, p = 0.750), molecular complete response (20.5% vs. 22.0%, p = 0.891), and early mortality rate (3.2% vs. 3.5%, p = 0.922) were similar between the TKIs with reduced-dose chemotherapy group and the TKIs with standard chemotherapy group. The proportions of lung infections, bloodstream infections, patients with >21 days of hospitalization, the total costs, transfusion costs, and antimicrobial costs were higher in the standard chemotherapy group than in the TKIs with reduced-dose chemotherapy group. The 3-year overall survival rates (59.0% [95% CI, 46.6–74.7%] vs. 38.4% [95% CI, 29.9–49.4%]) and disease-free survival rates (48.6% [95% CI, 34.2–69.1%] vs. 32.0% [95% CI, 23.5–43.7%]) were significantly better in the transplant group than in the non-transplant group. Conclusion: An induction regimen combining TKIs with reduced-dose chemotherapy and transplantation during the first complete remission remains a suitable and effective option for patients with Ph+ ALL.

TCP1, one of the subunits of molecular chaperone containing tailless complex polypeptide 1 (CCT) (CCT1), maybe play an essential role in cell proliferation and tumorigenesis. However, the biological functions and the underlying mechanisms of TCP1 in tumors are not fully understood. Here, we found that TCP1 levels increased with successive generations of xenografted tumors and were associated with the tumorigenicity of HL-60 cells. TCP1 expression was significantly higher in de novo and recurrent leukemia clinical samples and in various solid tumor tissues than in their related normal tissues. High expression of TCP1 was significantly associated with poor outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) and HCC. Functional assays and mechanistic studies revealed that TCP1 suppression not only decreased the proliferation and invasion of cancer cells in vitro but also inhibited tumor growth and metastatic spread in vivo. Ubiquitination assays and mechanistic studies revealed that TCP1 regulated the stability of c-Myc through the AKT/GSK-3β and ERK signaling pathways. Moreover, TCP1 knockin (TCP1-KI) mice, which generated by CRISPR/Cas9-mediated genome engineering, dramatically facilitated the occurrence of DEN-induced HCC. Our results demonstrate a novel mechanism of TCP1 regulation in multiple malignant tumors, and targeting TCP1 may provide new therapeutic strategies for the cancer treatment.