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ResearchIn-Press PreviewGeneticsOncology Open Access | 10.1172/JCI195929

Overexpression of the signaling-coordinator GAB2 can play an important role in Acute Myeloid Leukemia progression

Michael H. Kramer,1 Stephanie N. Richardson,1 Yang Li,1 Tiankai Yin,1 Nichole M. Helton,1 Daniel R. George,1 Michelle Cai,1 Sai Mukund Ramakrishnan,1 Casey D.S. Katerndahl,1 Christopher A. Miller,1 and Timothy J. Ley1

1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, United States of America

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Published August 7, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI195929.
Copyright © 2025, Kramer et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 7, 2025 - Version history
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Abstract

Mutations that initiate AML can cause clonal expansion without transformation (“clonal hematopoiesis”). Cooperating mutations, usually in signaling genes, are needed to cause overt disease, but these may require a specific “fitness state” to be tolerated. Here, we show that nearly all AMLs arising in a mouse model expressing two common AML initiating mutations (Dnmt3aR878H and Npm1cA) acquire a single copy amplification of chromosome 7, followed by activating mutations in signaling genes. We show that overexpression of a single gene on chromosome 7 (Gab2, which coordinates signaling pathways) is tolerated in the presence of the Npm1cA mutation, can accelerate the development of AML, and is important for survival of fully transformed AML cells. GAB2 is likewise overexpressed in many human AMLs with mutations in NPM1 and/or signaling genes, and also in Acute Promyelocytic Leukemia initiated by PML::RARA; the PML::RARA fusion protein may activate GAB2 by directly binding to its 5′ flanking region. A similar pattern of GAB2 overexpression preceding mutations in signaling genes has been described in other human malignancies. GAB2 overexpression may represent an oncogene-driven adaptation that facilitates the action of signaling mutations, suggesting an important (and potentially targetable) “missing link” between the initiating and progression mutations associated with AML.

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