YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies.

Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis.

GPR68 supports AML cells through the calcium/calcineurin pro-survival pathway and confers chemoresistance by mediating glucose metabolic symbiosis.

Accumulating evidence demonstrates that the "Warburg effect" that glycolysis is enhanced even in the presence of oxygen existed in hematopoietic malignancies, contributing to extracellular acidosis. G-protein coupled receptor 68 (GPR68), as a proton sensing GPCR responding to extracellular acidosis, is expected to play a critical role in hematopoietic malignancies. In the present study, we found that GPR68 was overexpressed in acute myeloid leukemia (AML) cells, and GPR68 deficiency impaired AML cell survival in vitro and cell engraftment in vivo.

Chemotherapy resistance in acute myeloid leukemia is mediated by A20 suppression of spontaneous necroptosis.

Acute myeloid leukemia (AML) is a deadly hematopoietic malignancy. Although many patients achieve complete remission with standard induction therapy, a combination of cytarabine and anthracycline, ~40% of patients have induction failure. These refractory patients pose a treatment challenge, as they do not respond to salvage therapy or allogeneic stem cell transplant.