Mechanisms of Chemotherapy Failure in Refractory/Relapsed Acute Myeloid Leukemia: The Role of Cytarabine Resistance and Mitochondrial Metabolism

ABSTRACT: Acute myeloid leukemia (AML) originates from malignant, immature myeloid progenitor cells that differentiate into dysfunctional myeloblasts. While cytarabine (Ara-C) and daunorubicin (DNR)-based chemotherapy regimens are the standard treatments, approximately 10-40% of AML patients under the age of 60 and 40-60% over 60 do not respond, leading to refractory or relapsed (R/R) AML. Targeted chemotherapy for FLT3-ITD mutated R/R AML cells improves response rates and survival outcomes in FLT3-ITD mutated R/R AML patients. However, patients with wild-type FLT3 R/R AML remain therapeutically challenged, with persistent difficulty in finding effective treatments. Better insights on the fundamental understanding of treatment failure in wild-type FLT3 AML cells are needed to enhance therapeutic outcomes. However, precise mechanisms behind the treatment failure remain unclear. This study investigates the mechanisms underlying the failure of Ara-C and DNR-based chemotherapy in wild-type FLT3 R/R AML. Using RHI-1 cells, a wild-type FLT3 AML cell line with Ara-C resistance, we demonstrated that Ara-C resistance-mediated DNR tolerance did not result from reducing the concentration of DNR in RHI-1 cells, but rather from interrupting the cytotoxic mechanisms of DNR through the Ara-C resistance of RHI-1. The down-regulated deoxycytidine kinase (DCK) in RHI-1 cells interrupted mechanisms of Ara-C cytotoxic action. Also, the down-regulation of DCK enhanced mitochondrial metabolic pathways, DNA repair process, and ROS detoxification. Through these pathways, RHI-1 cells exhibit tolerance under DNR treatment. Among these enhanced processes, targeting mitochondrial metabolism, particularly OXPHOS complex I proteins, improved the efficacy of both Ara-C and DNR. Our findings shed light on a potential mechanism underlying the treatment failure and the role of mitochondrial metabolism in wild-type FLT3 R/R AML cells.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte

DISEASE(S): Acute Leukemia

SUBMITTER: Jong-Seo Kim  

LAB HEAD: Jong-Seo Kim

PROVIDER: PXD054797 | Pride | 2025-05-07

REPOSITORIES: Pride