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In this study, we perform unbiased genetic screens to identify GAPs and GEFs with cancer- and lineage-specific requirements, as well as dual perturbation screens to dissect functionally relevant interactors of GAPs and GEFs. Application to primary specimens from patients with acute myeloid leukemia uncovers the GAP ARHGAP45 as a targetable dependency shared across cancers of hematopoietic origin while being dispensable in normal hematopoiesis. We demonstrate that targeting ARHGAP45-expressing cells can be achieved through T-cell receptor chimeric antigen receptor T cells directed at an ARHGAP45-encoded minor histocompatibility antigen and that pharmacologic targeting of CDC42 required upon ARHGAP45 depletion augments ARHGAP45-directed cell therapies. These studies provide a resource for probing oncogenic and druggable regulators of GTPases and strategies to target a GAP that represents a shared dependency across blood cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>In this study, we systematically interrogated GAPs and GEFs in cancer and identified the GAP ARHGAP45 as a dependency shared across blood cancers while dispensable in normal hematopoiesis. Targeting ARHGAP45-expressing cells is achievable via T-cell receptor chimeric antigen receptor T cells directed at an ARHGAP45-derived antigen and small-molecule inhibition of GTPases required upon ARHGAP45 loss.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0299","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T14:22:54Z","timestamp":1754922174000},"page":"2530-2553","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Systematic Evaluation of GAPs and GEFs Identifies a Targetable Dependency for Hematopoietic Malignancies"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1548-2087","authenticated-orcid":false,"given":"Pu","family":"Zhang","sequence":"first","affiliation":[{"name":"1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8189-0169","authenticated-orcid":false,"given":"Zhendong","family":"Cao","sequence":"additional","affiliation":[{"name":"2Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."},{"name":"3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2537-6616","authenticated-orcid":false,"given":"Xiangyu","family":"Pan","sequence":"additional","affiliation":[{"name":"4Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8868-9022","authenticated-orcid":false,"given":"Yuqiao","family":"Liu","sequence":"additional","affiliation":[{"name":"2Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7626-8903","authenticated-orcid":false,"given":"Cynthia","family":"Castro","sequence":"additional","affiliation":[{"name":"1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1816-6119","authenticated-orcid":false,"given":"Won Jun","family":"Kim","sequence":"additional","affiliation":[{"name":"1Molecular Pharmacology Program, Sloan 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