<scp>CRTC2</scp> Promotes <scp>AML</scp> Progression and Mediates Mitochondrially‐Driven Venetoclax Resistance

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the malignant proliferation of myeloid progenitor cells. Although the introduction of the B-cell lymphoma-2 (BCL-2) inhibitor Venetoclax (VEN) has significantly improved patient outcomes and established it as a first-line treatment, high rates of drug resistance and relapse remain major clinical challenges. We integrated RUNX3 chromatin immunoprecipitation sequencing (ChIP-seq) data with the GAPIA2 database to identify CRTC2 as a key candidate gene. Subsequently, we employed qRT-PCR to compare CRTC2 expression levels between donors and AML patients. The role of CRTC2 in apoptosis was further validated through knockdown and overexpression experiments in various cell lines. To investigate the impact of CRTC2 on AML progression, we established a cell line-derived xenograft (CDX) model. The proportion of human CD45-positive (hCD45⁺) cells in the bone marrow and liver was assessed, and histological examination was conducted using HE staining, along with peripheral blood smear analysis. In addressing VEN resistance, we analyzed CRTC2 expression patterns in clinical samples and explored the synergistic therapeutic effect of a CRTC2 inhibitor in combination with VEN. To further elucidate the underlying molecular mechanisms, we performed mitochondrial function assays and analyzed mitochondrial translation-related proteins. Clinical analyses have demonstrated that elevated expression levels of CRTC2, a downstream target of RUNX3, are significantly correlated with poor prognosis in patients with AML. Functional experiments have shown that CRTC2 plays a role in disease progression by modulating apoptosis in AML cells. The knockdown of CRTC2 was observed to delay disease progression in CDX mouse models. Additional investigations revealed a positive correlation between CRTC2 expression and resistance to VEN in AML cells, with CRTC2 inhibition synergistically enhancing VEN's cytotoxic effects. Mechanistic studies suggest that increased mitochondrial activity contributes to VEN resistance, thereby identifying a potential molecular target for overcoming drug resistance. CRTC2 is a key regulator in AML, with high expression levels promoting disease progression and resistance to VEN. Inhibiting CRTC2 reduces mitochondrial translation and energy reserves, increasing AML cell sensitivity to VEN. These results highlight CRTC2 as a promising therapeutic target and suggest a new strategy to overcome VEN resistance.