Effects of Triad1-knockdown on ribosome/polysome profiles are reversed by Gcn1-knockdown

Previously, we identified ARIH2, the gene encoding Triad1, as a HoxA10 target gene. We found that HoxA10-induced expression of Triad1 was necessary for termination of emergency granulopoiesis, and antagonized leukemogenesis in a murine model of KMT2A-rearranged AML. In this study, we found that knockdown Triad1 increased polysome-specific mRNAs regulating the cellular response to stress, the DNA-damage response, ribosomal biogenesis, or protein catabolism, but decreased mRNAs regulating mitosis, DNA-repair, DNA and RNA metabolism, or Tp53 activity in U937 cells. Polysome-specific mRNAs for Solute Carrier Proteins (SLCs) were also increased by Triad1-knockdown, consistent with correction of metabolic defects during the ISR. This included SLCs involved in import of amino acids, long chain fatty acids and glucose, and lactate export. In comparison of polysome-specific mRNA profiles with Triad1-knockdown versus knockdown of Triad1 plus Gcn1, we identified the same gene and pathway differences as in comparison of Triad1-knockdown to control cells. There were only minor differences in polysome specific mRNAs in cells with Triad1- plus Gcn1-knockdown versus control cells, encompassing fewer differences than with Triad1-knockdown alone. This suggested that Triad1-knockdown on ribosome/polysome profiles are reversed by Gcn1-knockdown in U937 cells.