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Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE253753 | GEO | 2024/05/15

REPOSITORIES: GEO

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Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia [ATAC-seq]

Project description:MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with RUNX1::RUNX1T1, however, very little is known about the impact of these MGA alterations on normal hematopoiesis or disease progression. We show that representative MGA mutations identified in patient samples abolish protein-protein interactions and transcriptional activity. Using a series of human and mouse model systems, including a newly developed conditional knock-out mouse strain, we demonstrate that loss of MGA results in upregulation of MYC and E2F targets, cell cycle genes, mTOR signaling, and oxidative phosphorylation in normal hematopoietic cells, leading to enhanced proliferation. The loss of MGA induces an open chromatin state at promotors of genes involved in cell cycle and proliferation. RUNX1::RUNX1T1 expression in Mga-deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1T1 fusion oncoprotein to enhance leukemogenesis.

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Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia [Cut&Run]

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Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia [RNA-seq]

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Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia

Project description:Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia

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Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia [RNA-seq]

Project description:Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia [RNA-seq]

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Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia [ATAC-seq]

Project description:Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia [ATAC-seq]

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Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia [Cut&Run]

Project description:Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia [Cut&Run]

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Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations.

Project description:Acute myeloid leukemia (AML) with t(8;21) (q22;q22) is considered to have favorable risk; however, nearly half of t(8;21) patients are not cured, and recent studies have highlighted remarkable genetic heterogeneity in this subset of AML. Here we identify somatic mutations in additional sex combs-like 2 (ASXL2) in 22.7% (25/110) of patients with t(8;21), but not in patients with inv(16)/t(16;16) (0/60) or RUNX1-mutated AML (0/26). ASXL2 mutations were similarly frequent in adults and children t(8;21) and were mutually exclusive with ASXL1 mutations. Although overall survival was similar between ASXL1 and ASXL2 mutant t(8;21) AML patients and their wild-type counterparts, patients with ASXL1 or ASXL2 mutations had a cumulative incidence of relapse of 54.6% and 36.0%, respectively, compared with 25% in ASXL1/2 wild-type counterparts (P = .226). These results identify a high-frequency mutation in t(8;21) AML and identify the need for future studies to investigate the clinical and biological relevance of ASXL2 mutations in this unique subset of AML.

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Project description:The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1-RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1-RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1-RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.

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Mediation analysis reveals common mechanisms of RUNX1 point mutations and RUNX1/RUNX1T1 fusions influencing survival of patients with acute myeloid leukemia.

Project description:Alterations of RUNX1 in acute myeloid leukemia (AML) are associated with either a more favorable outcome in the case of the RUNX1/RUNX1T1 fusion or unfavorable prognosis in the case of point mutations. In this project we aimed to identify genes responsible for the observed differences in outcome that are common to both RUNX1 alterations. Analyzing four AML gene expression data sets (n = 1514), a total of 80 patients with RUNX1/RUNX1T1 and 156 patients with point mutations in RUNX1 were compared. Using the statistical tool of mediation analysis we identified the genes CD109, HOPX, and KIAA0125 as candidates for mediator genes. In an analysis of an independent validation cohort, KIAA0125 again showed a significant influence with respect to the impact of the RUNX1/RUNX1T1 fusion. While there were no significant results for the other two genes in this smaller validation cohort, the observed relations linked with mediation effects (i.e., those between alterations, gene expression and survival) were almost without exception as strong as in the main analysis. Our analysis demonstrates that mediation analysis is a powerful tool in the identification of regulative networks in AML subgroups and could be further used to characterize the influence of genetic alterations.

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