BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP

Abstract

AbstractsImatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but the primary and acquired imatinib resistance remains the big hurdle. Molecular mechanisms for CML resistance to tyrosine kinase inhibitors, beyond point mutations in BCR-ABL kinase domain, still need to be addressed. Here, we demonstrated that thioredoxin-interacting protein (TXNIP) is a novel BCR-ABL target gene. Suppression of TXNIP was responsible for BCR-ABL triggered glucose metabolic reprogramming and mitochondrial homeostasis. Mechanistically, Miz-1/P300 complex transactivates TXNIP through the recognition of TXNIP core promoter region, responding to the c-Myc suppression by either imatinib or BCR-ABL knockdown. TXNIP restoration sensitizes CML cells to imatinib treatment and compromises imatinib resistant CML cell survival, predominantly through the blockage of both glycolysis and glucose oxidation which results in the mitochondrial dysfunction and ATP production. In particular, TXNIP suppresses expressions of the key glycolytic enzyme, hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), potentially through Fbw7-dependent c-Myc degradation. In accordance, BCR-ABL suppression of TXNIP provided a novel survival pathway for the transformation of mouse bone marrow cells. Knockout of TXNIP accelerated BCR-ABL transformation, whereas TXNIP overexpression suppressed this transformation. Combination of drug inducing TXNIP expression with imatinib synergistically kills CML cells from patients and further extends the survival of CML mice. Thus, the activation of TXNIP represents an effective strategy for CML treatment to overcome resistance.

DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP

“…Among the remaining genes that were identified, upregulated SOD2 and IL8 are reported to promote rather than inhibit glucose transport/glycolysis [ 32 , 33 , 34 ], while we found no reports regarding such activities for upregulated FN1 , IL1A , ICAM1 and KDM5B-AS1 or for downregulated NAV2. In contrast, for the remaining upregulated gene, the tumor suppressor TXNIP (thioredoxin-interacting protein), a robust literature describes inhibition of glucose uptake [ 35 , 36 , 37 , 38 , 39 , 40 ] and glycolysis [ 40 , 41 , 42 , 43 ].…”

“…Our prior findings indicate that Dpep triggers a context-dependent cascade of altered transcription factor expression in cancer cells [ 16 ], thus raising the possibility of an indirect transcriptional mechanism. Multiple mechanisms and pathways have been described by which TXNIP expression can be regulated [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”