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 5

Some RTK/RAS signaling proteins display posttranscriptionally increased protein abundance and NPM1cA physical interactions.

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Some RTK/RAS signaling proteins display posttranscriptionally increased ...
(A) Mean expression values of protein and mRNA as measured in leukemic mAML murine bone marrow. Protein expression was measured using LFQ mass spectrometry. The R2 value was calculated on proteins and genes detected using both methods. S100a9 and S100a8 are known to be highly abundant genes/proteins in myeloid cells. Gab2 is indicated in red. (B) Hierarchical clustering of TMT proteomics data from preleukemic versus leukemic samples of the indicated genotypes using the unweighted pair group with arithmetic mean (UPGMA) method (76) and Pearson’s correlation of protein abundance profiles as the distance metric. A yellow box highlights preleukemic samples, and a blue box highlights AML samples. (C) t-SNE created from TMT proteomics data collected from murine bone marrow samples of the indicated types (annotated by color). Preleukemic and leukemic cells formed distinct clusters. mAML samples for B–F represent 2 biological replicates each of mAML 1 and mAML 3, transplanted into secondary recipients. (D–F) TMT protein abundance for the indicated genes from bone marrow of preleukemic and leukemic (mAML) mice from this model. Each dot represents a measurement from an individual mouse. TMT protein expression values were median centered at 0 and log2 transformed. For mAML samples, adjusted **P < 0.05, by t test with Benjamini-Hochberg multiple hypothesis correction for differences compared with Dnmt3aR878H/+ × Npm1cA/+ preleukemic bone marrow. Red lines indicate the mean of each group. (G–I) mRNA expression of the indicated genes from whole bone marrow of preleukemic and leukemic (mAML) mice from this model. NS indicates no significant differential expression in the mAML groups compared with Dnmt3aR878H/+ × Npm1cA/+ preleukemic bone marrow. Red lines indicate the mean of each group. Data for PIK3CD are also presented in Supplemental Figure 5C (RNA) and Supplemental Figure 5H (protein).