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

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

PROVIDER: PRJNA1066869 | ENA |

REPOSITORIES: ENA

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

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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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 [ATAC-seq]

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| PRJNA1066868 | ENA

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Project description:Single-cell RNA sequencing analysis of RUNX1-RUNX1T1(9a) transformed c-kit positive cells with (Kat2a WT) and without Kat2a (Kat2a NULL). Lineage negative bone marrow cells were collected from Kat2a fl/fl Mx1-Cre-/- and Kat2a fl/fl Mx1-Cre +/- animals after pIpC treatment and transduced with RUNX1-RUNX1T1(9a) expressing retrovirus (reported by GFP expression). Cells were injected into irradiated C57BL6 mice and GFP positive c-Kit positive bone marrow cells collected 2 and 4 months after transplantation. Cells were processed for single-cell RNA sequencing library preparation (10X chromium single cell) and next gene sequencing following 10X genomics v2 protocol.

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