GAB2 couples genetic drivers and signaling networks in acute myeloid leukemia
Amanda Luvisotto, Lu Wang
Amanda Luvisotto, Lu Wang
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Commentary

GAB2 couples genetic drivers and signaling networks in acute myeloid leukemia

Abstract

In acute myeloid leukemia (AML), leukemogenesis is typically driven by the sequential acquisition of distinct classes of mutations that collaborate to transform normal hematopoietic stem and progenitor cells. The founding and cooperating mutations in AML are often in signaling genes and form functional partnerships with each other, each addressing complementary aspects of malignant transformation. In this issue of the JCI, Kramer et al. elaborate on the molecular pathogenesis of AML. By using a mouse bone marrow model bearing the common AML-initiating mutations in DNA methyltransferase 3 α (DNMT3A) and nucleophosmin 1 (NPM1), the work provides further evidence for the role of the signaling orchestrator GRB2-associated–binding protein 2 (GAB2) in AML progression, positioning GAB2 as a potential therapeutic target.

Authors

Amanda Luvisotto, Lu Wang

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Figure 1

GAB2 links initiating mutations and progression signaling in myeloid leukemogenesis.

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GAB2 links initiating mutations and progression signaling in myeloid leu...
AMLs arising in a mouse model expressing two common initiating mutations (Dnmt3aR878H and Npm1cA) frequently acquire a single-copy amplification of chromosome 7, which includes the Gab2 gene locus. Overexpression of Gab2, driven by genetic amplification and/or the PML:RARA fusion protein, can accelerate AML development and promote the survival of fully transformed AML cells. The unique GAB2 interactome formed in the presence of mutant NPM1 activates downstream AKT and ERK signaling in a posttranscriptional manner, highlighting a critical role for GAB2 as a potentially targetable “missing link” between AML-initiating mutations and RTK/RAS pathway mutations associated with AML progression.