The ubiquitin ligase Triad1 influences myeloid leukemogenesis by regulating the integrated stress response

Increased expression of a set of homeodomain transcription factors, including HoxA10, characterizes an adverse prognosis subtype of acute myeloid leukemia (AML). Examples of this subtype include AML with KMT2A or MYST3/CREBBP gene rearrangements, and an AML subset with normal cytogenetics. Previously, we identified ARIH2, the gene encoding Triad1, as a HoxA10 target gene. We determined that transcriptional activation of ARIH2 by HoxA10 was necessary to terminate emergency granulopoiesis during the innate immune response but also antagonized leukemogenesis in a murine model of KMT2A-rearranged AML. Triad1 expression progressively decreases during the latent period preceding AML in this model, and Triad1 knockdown accelerates AML development. Triad1 is an E3 ubiquitin ligase, and we found that knocking down Triad1 decreased protein ubiquitination in myeloid cells. Therefore, proteins with Triad1-dependent ubiquitination might regulate leukemogenesis and/or the innate immune response. By proteomic screen, we identified Triad1-dependent ubiquitination of a set of proteins that regulate the integrated stress response (ISR), including Gcn1. The ISR prevents metabolic exhaustion during sustained inflammation by decreasing total mRNA translation and global protein synthesis, while altering the translatome to correct metabolic deficiencies and inhibit apoptosis. In cells with Triad1-knockdown, we defined a translatome consistent with ISR-activation and reversed by co-knockdown of Gcn1. Gcn1-knockdown also delayed AML development in a KMT2A-rearranged murine model, and reversed the effects of Triad1-knockdown on leukemogenesis. These results suggest ISR-inhibition mediates Triad1-related leukemia suppression, and activation of the ISR enhances leukemogenesis in this adverse-prognosis AML subtype.