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In this study, we determined the frequency of secondary lesions in 28 iAMP21 BCP\u2010ALL patient samples and investigated cellular sensitivity for candidate\u2010targeted drugs. iAMP21 was enriched in <jats:italic>FLT3<\/jats:italic> aberrations (10.7% vs. 50.0%, <jats:italic>p<\/jats:italic>\u2009=\u20090.003) and <jats:italic>SH2B3<\/jats:italic> inactivation (7.14% vs. 46.4%, <jats:italic>p<\/jats:italic>\u2009=\u20090.002), compared with 28 B\u2010other cases, and these alterations co\u2010occurred in 21.4%. The occurrence of lesions in <jats:italic>CRLF2<\/jats:italic> and <jats:italic>IL7R<\/jats:italic> was similar between iAMP21 and B\u2010other cases (25% vs. 17.9%, <jats:italic>p<\/jats:italic>\u2009=\u20090.746 and 7.14% vs. 0%, <jats:italic>p<\/jats:italic>\u2009=\u20090.491 respectively) as were mutations in <jats:italic>JAK1<\/jats:italic> and <jats:italic>JAK2<\/jats:italic> (3.57% vs. 0% and 10.7% vs. 10.7%, <jats:italic>p<\/jats:italic>\u2009=\u20091 for both). Sensitivity to the FLT3 inhibitor gilteritinib did not differ between iAMP21 and B\u2010other cases irrespective of FLT3 status. However, iAMP21 samples harboring both <jats:italic>FLT3\u2010<\/jats:italic>ITD and <jats:italic>SH2B3<\/jats:italic> lesions showed the highest sensitivity. <jats:italic>CRLF2\u2010<\/jats:italic>rearranged iAMP21 samples were slightly more sensitive to JAK inhibitor ruxolitinib than those without, although a lack of sensitivity was present in 50% of iAMP21 cases. Trametinib sensitivity varied among iAMP21 samples with over half of iAMP21 samples being sensitive irrespective of RAS\u2010pathway mutation status or other secondary lesions. In summary, iAMP21 leukemias were enriched in <jats:italic>FLT3<\/jats:italic> and in <jats:italic>SH2B3<\/jats:italic> lesions, which when co\u2010occurring affected sensitivity to FLT3 inhibition by gilteritinib but not JAK inhibition by ruxolitinib. Together, our results suggest that FLT3 and RAS signaling inhibitors are of interest for further (pre)clinical evaluation in iAMP21 BCP\u2010ALL.<\/jats:p>","DOI":"10.1002\/hem3.70069","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T07:20:21Z","timestamp":1737444021000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Secondary lesions and sensitivity to signaling inhibitors in iAMP21 acute lymphoblastic leukemia"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5164-3047","authenticated-orcid":false,"given":"Femke M.","family":"Hormann","sequence":"first","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology Utrecht Netherlands"},{"name":"Oncode Institute Utrecht Netherlands"},{"name":"Department of Pediatric Oncology and Hematology Erasmus MC\u2010Sophia Children's Hospital Rotterdam 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