LARP1 Regulates Leukemogenesis of AML By Altering Cell Metabolism and mRNA Translation

The mammalian target of rapamycin (mTOR) plays a crucial role in the pathophysiology of various tumors. However, attempts to target mTOR for cancer treatment have often been met with limited success, potentially due to overlapping signaling pathways, including the recently identified CDK9 mTOR-like (CTORC) complexes. La-related protein 1 (LARP1) is a common interactor of both mTORC1 and CTORC2 and is known to regulate ribosome production by managing the translation of 5‘ terminal oligopyrimidine tract (5‘ TOP) mRNAs, which typically encode ribosomal proteins and translation factors. In this study, we confirm LARP1 as a target shared by mTORC1 and CTORC2, and we explore the molecular mechanisms through which it drives the progression of acute myeloid leukemia (AML). Using CRISPR/CAS9 technology, we generated LARP1 knockout (KO) AML cell lines. The loss of LARP1 expression significantly reduced the proliferation and leukemic progenitor potential of these AML cell lines both in vitro and in vivo AML xenografts. Furthermore, we observed that LARP1 KO cell lines showed increased sensitivity to conventional chemotherapy drugs such as Azacitidine, Cytarabine, and Venetoclax. Polysome profiling followed by RNA-seq was employed to compare global translation levels between LARP1 KO and control U937 cells treated with mTOR, CDK9 inhibitors, combination of both or vehicle control. Our results indicate that loss of LARP1 expression had similar effects to treatment of U937 AML cells with mTOR and CDK9 inhibitors on translation. Finally, we performed global metabolomics analysis by LC-MS of U937 cells treated with either mTOR, CDK9 inhibitors or their combination as well as LARP1 KO cells. The results reveal that loss of LARP1 as well as inhibition of mTOR and CDK9 by small molecule antagonists diminish levels of some important oncometabolites. Altogether our findings suggest that LARP1 could be a potential therapeutic target for AML and warrants future drug discovery efforts to create LARP1 targeting small molecules.

Small:AbbVie: Other: Spouse is an employee and current equity holder .