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TRAF6 is a tumor suppressor in AML by directly targeting MYC oncogenic activity [RNA-Seq]

ABSTRACT: Clonal hematopoiesis of indeterminant potential (CHIP) is an aging-associated condition characterized by the clonal outgrowth of self-renewing cells that acquire specific mutations. One of the most frequent mutations in CHIP targets the methylcytosine dioxygenase TET2, also observed in number of myeloid neoplasms 1,2. Although individuals with CHIP are healthy, they are at an increased risk of developing hematopoietic malignancies. These findings indicate that additional alterations are needed for the transition from a pre-leukemic (CHIP) stage to frank leukemia, although the identity of such molecular events remains poorly characterized. To identify signaling states that cooperate with CHIP mutant cells we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitin ligase TRAF6. We demonstrate that TRAF6 is repressed in a subset of acute myeloid leukemia (AML) and myeloproliferative neoplasm (MPN) patients. Loss of TRAF6 in pre-leukemic HSPC results in overt AML/MPN and is associated with induction of MYC-dependent leukemic stem cell signatures. TRAF6 represses MYC activity at enhancers due to the ubiquitination of MYC on Lysine (K)148. Ubiquitination of MYC on K148, does not affect protein stability but rather antagonizes acetylation of MYC on the same lysine and suppresses MYC oncogenic activity by preventing its DNA binding. Our results identify a novel tumor suppressor function for TRAF6 and demonstrate a novel mode of regulation of MYC oncogenic activity

ORGANISM(S): Mus musculus

PROVIDER: GSE189172 | GEO | 2022/01/01

REPOSITORIES: GEO

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Project description:The cellular origin and molecular progression towards aggressive cancers such as acute myeloid leukemia (AML) remain elusive. Clinically, Myelodysplastic syndromes (MDS) and related myeloproliferative neoplasias (MPN) disorders1-5 are believed to present as a precursor stage to lethal AML development. Despite the identification of cytogenetic abnormalities and increased activation of signaling in human MDS/MPN, specific pathways that either sustain or initiate disease progression and evolve into self-sustaining leukemic-initiating cells (L-ICs)13 have not been elucidated. Here we demonstrate that tissue specific loss of glycogen synthase kinase-3Î² (GSK3 betaÎ²) initiates the emergence of stable Pre-leukemic-ICs (PLIC) in vivo. In contrast to deletion or transgenic perturbation of pathways associated with AML eg. Î²-catenin/Wnt, serial transplantation of PL-IC produced abnormal hematological disease that phenotypically and molecularly resembles human MDS/MPN. PL-ICs were exclusively generated from GSK3 betaÎ² deficient hematopoietic stem cells (HSCs), indicating that disease initiation events collaborate with existing HSC self-renewal machinery. In the absence of GSK3 betaÎ², subsequent deletion of GSK3 betaÎ± caused rapid induction of L-ICs that give rise to lethal AML. As these processes were solely driven by dose-dependent deficiencies in GSK3 beta levels, our results suggest that perturbation of this pathway can sufficiently drive and recapitulate a step-wise progression of disease from HSCs to MDS/MPN and subsequent AML. Our study provides a molecular and cellular foundation to understand AML evolution from pre-leukemic precursors. We suggest that defining the molecular states of pre-neoplastic disease will allow patient stratification at early stages of MDS/MPN onset and aid in the development of therapeutic targeting of causal pathways responsible for the earliest stages of leukemic initiation events. 5 week post-transplanted recipient mice (CD45.1) with either Lin- bone marrow GSK3 alpha +/+ beta +/flx, alpha+/+ beta flx/flx, alpha -/- beta +/+ or alpha-/- beta fx/flx Rosa26-CreERTM cells (CD45.2) were induced 3 times with intraperitoneal injections of Tamoxifen (75mg/kg) at intervals of two to three days. Mice were sacrificed and analyzed 4 weeks after injection. Bone marrow lineage negative (Lin-), Sca1+, cKit+ cells were sorted from engrafted Lin- bone marrow GSK3 alpha +/+ beta +/flx, alpha+/+ beta flx/flx, alpha -/- beta +/+ or alpha-/- beta fx/flx cells for RNA extraction. Total RNA from purified populations was extracted and amplified as described previously (Shojaei et al., 2005). Amplified-labeled RNA was hybridized to Affymetrix Mouse Genome 430 2.0 Array.

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TRAF6 is a tumor suppressor in AML by directly targeting MYC oncogenic activity [RNA-Seq]

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