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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 (\n                    <jats:italic>Dnmt3a<\/jats:italic>\n                    <jats:sup>R878H<\/jats:sup>\n                    and\n                    <jats:italic>Npm1<\/jats:italic>\n                    <jats:sup>cA<\/jats:sup>\n                    ) 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 (\n                    <jats:italic>Gab2<\/jats:italic>\n                    , which coordinates signaling pathways) was tolerated in the presence of the\n                    <jats:italic>Npm1<\/jats:italic>\n                    <jats:sup>cA<\/jats:sup>\n                    mutation, could accelerate the development of AML, and was important for the survival of fully transformed AML cells.\n                    <jats:italic>GAB2<\/jats:italic>\n                    is likewise overexpressed in many human AMLs with mutations in\n                    <jats:italic>NPM1<\/jats:italic>\n                    and\/or signaling genes, and also in acute promyelocytic leukemia initiated by\n                    <jats:italic>PML::RARA<\/jats:italic>\n                    ; the PML::RARA fusion protein may activate\n                    <jats:italic>GAB2<\/jats:italic>\n                    by directly binding to its 5\u2032 flanking region. A similar pattern of GAB2 overexpression preceding mutations in signaling genes has been described in other human malignancies.\n                    <jats:italic>GAB2<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci195929","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T16:00:28Z","timestamp":1754582428000},"source":"Crossref","is-referenced-by-count":2,"title":["Overexpression of the signaling coordinator GAB2 can play an important role in acute myeloid leukemia progression"],"prefix":"10.1172","volume":"135","author":[{"given":"Michael H.","family":"Kramer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie N.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiankai","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nichole M.","family":"Helton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel R.","family":"George","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sai Mukund","family":"Ramakrishnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7522-1946","authenticated-orcid":true,"given":"Casey D.S.","family":"Katerndahl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4266-6700","authenticated-orcid":true,"given":"Christopher A.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9913-0520","authenticated-orcid":true,"given":"Timothy J.","family":"Ley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2019.04.005"},{"key":"B2","unstructured":"NIH. 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