Jeffery Klco, Melvin Thomas, Wenqing Qi, Michael Walsh, Jing Ma, Tamara Westover, Sherif Abdelhamed, Lauren Ezzell, Chandra Rolle, Emily Xiong, Wojciech Rosikiewicz, Beisi Xu, Shondra Pruett-Miller, Allister Loughran, Laura Janke
{"title":"RUNX1::RUNX1T1急性髓细胞白血病MGA协同突变的功能特征。","authors":"Jeffery Klco, Melvin Thomas, Wenqing Qi, Michael Walsh, Jing Ma, Tamara Westover, Sherif Abdelhamed, Lauren Ezzell, Chandra Rolle, Emily Xiong, Wojciech Rosikiewicz, Beisi Xu, Shondra Pruett-Miller, Allister Loughran, Laura Janke","doi":"10.21203/rs.3.rs-3315059/v1","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>MGA</i> have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with <i>RUNX1::RUNX1T1,</i> however, very little is known about the impact of these <i>MGA</i> alterations on normal hematopoiesis or disease progression. We show that representative <i>MGA</i> 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 <i>MGA</i> 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 <i>MGA</i> induces an open chromatin state at promotors of genes involved in cell cycle and proliferation. <i>RUNX1::RUNX1T1</i> 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::RUNX1 T1 fusion oncoprotein to enhance leukemogenesis.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543392/pdf/","citationCount":"0","resultStr":"{\"title\":\"Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.\",\"authors\":\"Jeffery Klco, Melvin Thomas, Wenqing Qi, Michael Walsh, Jing Ma, Tamara Westover, Sherif Abdelhamed, Lauren Ezzell, Chandra Rolle, Emily Xiong, Wojciech Rosikiewicz, Beisi Xu, Shondra Pruett-Miller, Allister Loughran, Laura Janke\",\"doi\":\"10.21203/rs.3.rs-3315059/v1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <i>MGA</i> have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with <i>RUNX1::RUNX1T1,</i> however, very little is known about the impact of these <i>MGA</i> alterations on normal hematopoiesis or disease progression. We show that representative <i>MGA</i> 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 <i>MGA</i> 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 <i>MGA</i> induces an open chromatin state at promotors of genes involved in cell cycle and proliferation. <i>RUNX1::RUNX1T1</i> 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::RUNX1 T1 fusion oncoprotein to enhance leukemogenesis.</p>\",\"PeriodicalId\":21039,\"journal\":{\"name\":\"Research Square\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-09-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543392/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Research Square\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.21203/rs.3.rs-3315059/v1\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Research Square","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.21203/rs.3.rs-3315059/v1","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.
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::RUNX1 T1 fusion oncoprotein to enhance leukemogenesis.