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.

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-ALL. Access through your institution Buy or subscribe

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ONCOGENIC RAS PROMOTES LEUKEMIC TRANSFORMATION OF CUX1-DEFICIENT CELLS Article 01 February 2023 _RAS_ MUTATIONS DRIVE PROLIFERATIVE CHRONIC MYELOMONOCYTIC LEUKEMIA VIA A KMT2A-PLK1 AXIS

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gene expression. PLoS Biol. 2003;1:E53. Article  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by an Alex’ Lemonade Stand Foundation Innovator Award, the

NIH/NCI (R01 – CA187318), and the NIH/NHLBI (R01 – HL120724) (all to JPR). Further support came from a Leukemia & Lymphoma Society grant (to MM) and the Rothschild Fellowship for

postdoctoral fellows in the Natural, Exact or Life Sciences and Engineering (to LK), and PD is a Mark Foundation Momentum Fellow supported by a fellowship from the Mark Foundation for Cancer

Research; and by NCI grants CA021765 (St Jude Comprehensive Cancer Center Support Grant), an NCI R35 Outstanding Investigator Award (R35 CA197695) and a St. Baldrick’s Foundation Robert J.

Arceci Innovation award. We thank the members of the Roose lab and the Heme-Onc community at UCSF for useful suggestions and comments. We thank UCSF flow cytometry facility and DRC Center

Grant NIH P30 DK063720. We thank Emmanuelle Passague and her lab for kindly providing us _Mx1-CRE_ mice. AUTHOR INFORMATION Author notes * Olga Ksionda Present address: Liggins Institute,

The University of Auckland, Auckland, New Zealand * Marsilius Mues Present address: Miltenyi Biotec GmbH, Friedrich-Ebert-Str. 68, 51429, Bergisch Gladbach, Germany * These authors

contributed equally: Laila Karra, Damia Romero-Moya, Olga Ksionda AUTHORS AND AFFILIATIONS * Department of Anatomy, University of California, San Francisco, San Francisco, CA, 94143, USA

Laila Karra, Damia Romero-Moya, Olga Ksionda, Milana Krush, Marsilius Mues, Philippe Depeille & Jeroen P. Roose * Department of Pathology and Hematological Malignancies Program, St. Jude

Children’s Research Hospital, Memphis, TN, 38105, USA Zhaohui Gu & Charles Mullighan Authors * Laila Karra View author publications You can also search for this author inPubMed Google

Scholar * Damia Romero-Moya View author publications You can also search for this author inPubMed Google Scholar * Olga Ksionda View author publications You can also search for this author

inPubMed Google Scholar * Milana Krush View author publications You can also search for this author inPubMed Google Scholar * Zhaohui Gu View author publications You can also search for this

author inPubMed Google Scholar * Marsilius Mues View author publications You can also search for this author inPubMed Google Scholar * Philippe Depeille View author publications You can

also search for this author inPubMed Google Scholar * Charles Mullighan View author publications You can also search for this author inPubMed Google Scholar * Jeroen P. Roose View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS LK, DR-M, OK, and MM performed experiments and analyzed results. PD made the mouse construct. ZG and

CGM generated and analyzed human T-ALL genomic data. LK and DR-M. made the figures; JR designed the research and secured the majority of the funding. LK, DR-M, and JR wrote the paper.

CORRESPONDING AUTHOR Correspondence to Jeroen P. Roose. ETHICS DECLARATIONS CONFLICT OF INTEREST Jeroen Roose is a co-founder and scientific advisor of Seal Biosciences, Inc. and on the

scientific advisory committee for the Mark Foundation for Cancer Research. C.G.M. receives research funding from Loxo Oncology, Abbvie, and Pfizer, and speaking fees from Amgen. ADDITIONAL

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Karra, L., Romero-Moya, D., Ksionda, O. _et al._ Increased baseline RASGRP1 signals enhance stem cell fitness during native hematopoiesis.

_Oncogene_ 39, 6920–6934 (2020). https://doi.org/10.1038/s41388-020-01469-8 Download citation * Received: 14 May 2020 * Accepted: 10 September 2020 * Published: 28 September 2020 * Issue

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