Targeting branched-chain amino acid metabolism for the treatment of chronic myeloid leukemia
Location
E4110
Document Type
Poster
Start Date
30-11-2023 1:05 PM
End Date
30-11-2023 1:45 PM
Description
Abstract
Chronic myeloid leukemia (CML) is caused by a chimeric fusion of human chromosomes 9 and 22. This produces a hybrid BCR-ABL tyrosine kinase that drives abnormal myeloid cell proliferation. BCR-ABL positive CML is treated with tyrosine kinase inhibitors (TKIs). Mutations in the BCR-ABL gene chimera reduce the efficacy of TKIs. Our study aimed to target genes influencing CML metabolism as a new approach to overcome CML resistance to TKIs. We focused on the branched-chain amino acid (BCAA) metabolism since it stimulates CML growth. By using the eukaryotic promoter database (EPD) we found that the transcription factor JUN-B has putative binding sites in the promoter regions of 4 genes in BCAA metabolism, BCAT1, BCAT2, BCKDHA and DBT. JUN-B induces apoptosis, but it is silenced in CML. CML specimens, collected before (baseline, n=135) or after treatment with 400mg (n=30) and 800mg (n=33) Imatinib (TKI), were obtained from the R2-genomic analysis platform. T-test analysis tested the difference between the gene expression of JUN-B and the BCAA metabolic genes. In baseline specimens, there was a significant negative correlation between the expression of JUN-B and BCAT1/BCAT2 suggesting that JUN-B is their negative regulator in CML. Treatment with Imatinib reduced the expression of BCAT1 but not that of BCAT2, BCKDHA or DBT. Results suggest that BCAT1 and BCAT2 are downstream targets of JUN-B and Imatinib may reduce the burden of CML by downregulating the expression of BCAT1. These findings provided the background to investigate the mechanism of targeting BCAA metabolism in CML in TKI resistant patients.
Recommended Citation
Swain, Maxwell and Ananieva, Elitsa, "Targeting branched-chain amino acid metabolism for the treatment of chronic myeloid leukemia" (2023). DMU Research Symposium. 31.
https://digitalcommons.dmu.edu/researchsymposium/2023rs/2023abstracts/31
Targeting branched-chain amino acid metabolism for the treatment of chronic myeloid leukemia
E4110
Abstract
Chronic myeloid leukemia (CML) is caused by a chimeric fusion of human chromosomes 9 and 22. This produces a hybrid BCR-ABL tyrosine kinase that drives abnormal myeloid cell proliferation. BCR-ABL positive CML is treated with tyrosine kinase inhibitors (TKIs). Mutations in the BCR-ABL gene chimera reduce the efficacy of TKIs. Our study aimed to target genes influencing CML metabolism as a new approach to overcome CML resistance to TKIs. We focused on the branched-chain amino acid (BCAA) metabolism since it stimulates CML growth. By using the eukaryotic promoter database (EPD) we found that the transcription factor JUN-B has putative binding sites in the promoter regions of 4 genes in BCAA metabolism, BCAT1, BCAT2, BCKDHA and DBT. JUN-B induces apoptosis, but it is silenced in CML. CML specimens, collected before (baseline, n=135) or after treatment with 400mg (n=30) and 800mg (n=33) Imatinib (TKI), were obtained from the R2-genomic analysis platform. T-test analysis tested the difference between the gene expression of JUN-B and the BCAA metabolic genes. In baseline specimens, there was a significant negative correlation between the expression of JUN-B and BCAT1/BCAT2 suggesting that JUN-B is their negative regulator in CML. Treatment with Imatinib reduced the expression of BCAT1 but not that of BCAT2, BCKDHA or DBT. Results suggest that BCAT1 and BCAT2 are downstream targets of JUN-B and Imatinib may reduce the burden of CML by downregulating the expression of BCAT1. These findings provided the background to investigate the mechanism of targeting BCAA metabolism in CML in TKI resistant patients.
