Aberrant BCAT1 expression augments mTOR activity and accelerates disease progression in Chronic Lymphocytic leukemia

ABSTRACT: To identify genes contributing to the pathobiology of CLL, we performed gene expression profiling of mRNA/cDNA isolated from N=117 flow sorted CLL and detected aberrant expression of the metabolic enzyme branched chain amino acid transferase (BCAT1) in CLL with del17p/TP53mut. We performed immunoblotting in 205 and Q-PCR in 269 CLL samples and confirmed the highly preferential expression of BCAT1 in CLL with del17p/TP53mut (66%) or trisomy 12 (77%), and largely absent expression in CLL with del13q14 (15%) or normal FISH (29%). BCAT1 was not expressed in normal human lymph node derived B cells. The products of the bidirectional BCAT1 reaction, including leucine, acetyl-CoA, and alpha-ketoglutarate are activators of MTOR. We measured an ~2-fold higher MTOR activity via normalized p-S6K levels in CLL with BCAT1 high versus absent expression before and after sIgM crosslinking, which was abolished following pretreatment with a specific BCAT1 inhibitor. We performed steady state metabolomics and heavy isoptope metabolic tracing in primary CLL cells, demonstrating that CLL cells are avid consumers of branched chain aminoacids (BCAAs) and that BCAT1 in CLL engages in rapid bidirectional substrate utilization. Biologically, three CLL-derived cell lines with targeted disruption of BCAT1 had substantially reduced growth ex vivo. Further, CLL with aberrant BCAT1 expression were less sensitive to Venetoclax-induced apoptosis. Clinically, the expression of any BCAT1 protein in CLL resulted in shorter median survival than in CLL without BCAT1 expression (125 mo versus 296 mo; p<0.0001), even after exclusion of del17p/TP53mut cases (193 mo versus 296 mo; p<0.003).

ORGANISM(S): Homo sapiens

PROVIDER: GSE239832 | GEO | 2024/12/23

REPOSITORIES: GEO