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Through genome-wide mutational and transcriptional analyses of 177\n                  <jats:italic>NUP98<\/jats:italic>\n                  -rearranged leukemias, we show that cooperating alterations are associated with differentiation status even among leukemias sharing the same\n                  <jats:italic>NUP98<\/jats:italic>\n                  fusions, such as\n                  <jats:italic>NUP98::KDM5A<\/jats:italic>\n                  acute megakaryocytic leukemia with\n                  <jats:italic>RB1<\/jats:italic>\n                  loss or T-cell acute lymphoblastic leukemia with\n                  <jats:italic>NOTCH1<\/jats:italic>\n                  mutations. CUT&amp;RUN profiling reveals that NUP98 fusion oncoproteins directly regulate differentiation-related genes, with binding patterns also influenced by differentiation stage. Using\n                  <jats:italic>in vitro<\/jats:italic>\n                  models, we show\n                  <jats:italic>RB1<\/jats:italic>\n                  loss cooperates with NUP98::KDM5A by blocking terminal differentiation toward platelets and expanding megakaryocyte-like cells, whereas\n                  <jats:italic>WT1<\/jats:italic>\n                  frameshifts skew differentiation toward dormant lympho-myeloid primed progenitor cells and cycling granulocyte-monocyte progenitor cells. NUP98::KDM5A models with\n                  <jats:italic>RB1<\/jats:italic>\n                  or\n                  <jats:italic>WT1<\/jats:italic>\n                  alterations have different sensitivities to menin inhibition, suggesting cellular differentiation stage-specific resistant mechanism against menin inhibitors with clinical implications for\n                  <jats:italic>NUP98<\/jats:italic>\n                  -rearranged leukemia.\n                <\/jats:p>","DOI":"10.1101\/2025.01.21.25320683","type":"posted-content","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T18:10:14Z","timestamp":1737569414000},"source":"Crossref","is-referenced-by-count":2,"title":["Fusion oncoproteins and cooperating mutations define disease phenotypes in\n                  <i>NUP98<\/i>\n                  -rearranged 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