{"doi":"10.1101/2020.06.24.169631","title":"Increased baseline RASGRP1 signals Enhance Stem Cell Fitness during Native Hematopoiesis","abstract":"Abstract Oncogenic mutations in RAS genes, like KRAS G12D or NRAS G12D , trap Ras in the active state and cause myeloproliferative disorder and T cell leukemia (T-ALL) when induced in the bone marrow via Mx1CRE . The RAS exchange factor RASGRP1 is frequently overexpressed in T-ALL patients. In T-ALL cell lines overexpression of RASGRP1 increases flux through the RASGTP/RasGDP cycle. Here we expanded RASGRP1 expression surveys in pediatric T-ALL and generated a RoLoRiG mouse model crossed to Mx1CRE to determine the consequences of induced RASGRP1 overexpression in primary hematopoietic cells. RASGRP1-overexpressing, GFP-positive cells outcompeted wild type cells and dominated the peripheral blood compartment over time. RASGRP1 overexpression bestows gain-of-function colony formation properties to bone marrow progenitors in medium containing limited growth factors. RASGRP1 overexpression enhances baseline mTOR-S6 signaling in the bone marrow, but not in vitro cytokine-induced signals. In agreement with these mechanistic findings, hRASGRP1-ires-EGFP enhances fitness of stem- and progenitor- cells, but only in the context of native hematopoiesis. RASGRP1 overexpression is distinct from KRAS G12D or NRAS G12D , does not cause acute leukemia on its own, and leukemia virus insertion frequencies predict that RASGRP1 overexpression can effectively cooperate with lesions in many other genes to cause acute T cell leukemia.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126989,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":531940,"name":"Damià Romero–Moya","orcid":"0000-0001-9947-3577","position":1,"is_corresponding":false},{"id":532853,"name":"Olga Ksionda","orcid":null,"position":2,"is_corresponding":false},{"id":575061,"name":"Milana Krush","orcid":"0000-0003-4833-8564","position":3,"is_corresponding":false},{"id":253485,"name":"Zhaohui Gu","orcid":"0000-0003-1581-1327","position":4,"is_corresponding":false},{"id":575459,"name":"Marsilius Mues","orcid":null,"position":5,"is_corresponding":false},{"id":258123,"name":"Philippe Depeille","orcid":"0000-0002-5650-5521","position":6,"is_corresponding":false},{"id":247450,"name":"Charles G. Mullighan","orcid":"0000-0002-1871-1850","position":7,"is_corresponding":false},{"id":258125,"name":"Jeroen P. Roose","orcid":"0000-0003-4746-2811","position":8,"is_corresponding":false},{"id":575060,"name":"Laila Karra","orcid":"0000-0001-5503-2809","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:15:27.226519Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}