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

ABSTRACT: Increased expression of a set of homeodomain transcription factors, including HoxA10A, characterizes an adverse prognosis subtype of acute myeloid leukemia (AML). This increase in Hox expression may be found in AML with KMT2A or MYST3/CREBBP gene rearrangements, or with normal cytogenetics. Previously, we identified ARIH2, the gene encoding Triad1, as a HoxA10 target gene. We found 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 to AML in this model and Triad1-knockdown accelerates AML development. Since Triad1 is an E3 ubiquitin ligase, 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 protein synthesis, and altering the translatome to correct metabolic deficiencies and inhibit apoptosis. In cells with Triad1-knockdown, we defined a translatome that was consistent with ISR-activation and reversed by co-knockdown of Gcn1. Gcn1-knockdown also delayed development of AML in a KMT2A-rearranged murine model, and reversed effects of Triad1-knockdown. These results suggest ISR-inhibition mediates leukemia suppression by Triad1, and activation of the ISR enhances leukemogenesis in this adverse prognosis AML subtype.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Myeloid Cell

SUBMITTER: Peter Faull  

LAB HEAD: Peter Faull

PROVIDER: PXD060787 | Pride | 2025-08-25

REPOSITORIES: Pride