Overexpression of the signaling coordinator GAB2 can play an important role in acute myeloid leukemia progression
Michael H. Kramer, Stephanie N. Richardson, Yang Li, Tiankai Yin, Nichole M. Helton, Daniel R. George, Michelle Cai, Sai Mukund Ramakrishnan, Casey D.S. Katerndahl, Christopher A. Miller, Timothy J. Ley
Michael H. Kramer, Stephanie N. Richardson, Yang Li, Tiankai Yin, Nichole M. Helton, Daniel R. George, Michelle Cai, Sai Mukund Ramakrishnan, Casey D.S. Katerndahl, Christopher A. Miller, Timothy J. Ley
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Research Article Genetics Oncology

Overexpression of the signaling coordinator GAB2 can play an important role in acute myeloid leukemia progression

Abstract

Mutations that initiate acute myeloid leukemia (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 2 common AML-initiating mutations (Dnmt3aR878H and Npm1cA) acquired a single copy amplification of chromosome 7 (chr7), followed by activating mutations in signaling genes. We show that overexpression of a single gene on chr7 (Gab2, which coordinates signaling pathways) was tolerated in the presence of the Npm1cA mutation, could accelerate the development of AML, and was important for the 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.

Authors

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

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Figure 9

GAB2 mRNA abundance is increased by PML::RARA in both mouse and human hematopoietic cells.

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GAB2 mRNA abundance is increased by PML::RARA in both mouse and human h...
(A) Genome browser tracks for the Gab2 locus in mouse for anti-V5 ChIP-Seq or CUT&RUN performed in WT lineage–depleted mouse bone marrow cells transduced with PML::RARAWT-V5, compared with empty vector–transduced cells or cells transduced with a PML::RARAC88A-V5 mutant that does not bind to its consensus DNA target sites (50, 77, 78). Assay for transposase-accessible chromatin using sequencing (ATAC-Seq) was performed on promyelocytes that were flow-enriched from the bone marrow of Ctsg-PML::RARA mice or WT littermates. (B) Gab2 mRNA expression from bulk RNA-Seq on flow-sorted promyelocytes from three 8- to 12-week-old littermate-matched Ctsg-PML::RARA mice versus WT mice. **FDR = 1 × 10–14. (C) t-SNE plots of scRNA-Seq data from whole bone marrow cells from young, nonleukemic WT mice or Ctsg-PML::RARA mice (51). Known hematopoietic cell types are labeled according to Haemopedia gene expression profiling (79, 80). A unique population of myeloid precursor cells that were only present in the bone marrow from Ctsg-PML::RARA mice is outlined in blue (PML::RARA specific). Cells are colored according to Gab2 expression. GMPs, granulocyte-macrophage progenitors. DCs, dendritic cells. (D) Relative Gab2 expression by scRNA-Seq in the various lineage populations from C in WT versus Ctsg-PML::RARA (PR) bone marrow. **FDR = 1 × 10–15, ***FDR = 1 × 10–55. (E) Genome browser tracks for the GAB2 locus in humans for anti-V5 ChIP-Seq performed in healthy donor–derived (HD-derived), human CD34–enriched cord blood cells transduced with PML::RARAWT-V5, treated with DMSO or ATRA for 48 hours (50); ATRA degrades the PML::RARA protein (52). ATAC-Seq was performed in flow-sorted promyelocytes from healthy donors and in primary human APL samples.