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Mutations in protein tyrosine phosphatase (PTP) non\u2010receptor type 11 (PTPN11) and FMS like tyrosine kinase 3 with internal tandem duplication (FLT3\u2010ITD) are common in resistant patients and are linked to activation of mitogen\u2010activated protein kinase (MAPK) signalling and increased expression of anti\u2010apoptotic proteins such as myeloid cell leukaemia 1 (MCL\u20101) and b\u2010cell lymphoma\u2010extra large (BCL(x)L). Murine Ba\/F3 cells with different FLT3\u2010ITD variants were lentiviral transduced to express either wild\u2010type PTPN11 (Src\u2010homology 2 containing PTP) or the activating PTPN11\u2010E76K mutation. Cells were treated with VEN, the MCL\u20101 inhibitor S63845 and the mitogen\u2010activated protein kinase (MEK) inhibitor trametinib (TRA), alone or in combination. Additionally, primary AML samples were examined for drug sensitivity and protein expression profiles. Cells expressing PTPN11\u2010E76K showed marked resistance to VEN, coinciding with sustained extracellular signal\u2010regulated kinase activation and elevated MCL\u20101 and BCL(x)L levels. Combining VEN with MCL\u20101 inhibition significantly increased apoptosis. Co\u2010treatment with TRA provided substantial synergistic benefits while yielding a more modest benefit in PTPN11\u2010E76K\u2010mutant cells. Both PTPN11 and FLT3 mutations confer resistance in AML, making them key factors in identifying high\u2010risk patients. The presented results highlight the role of MAPK\u2010driven MCL\u20101 and BCL(x)L expression, which mediates VEN resistance. While dual inhibition of B\u2010cell lymphoma 2 and MCL\u20101 is already effective, additional MEK inhibition may further improve outcomes in PTPN11\u2010mutated AML.<\/jats:p>","DOI":"10.1111\/bjh.70344","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T11:29:25Z","timestamp":1769686165000},"page":"905-915","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting\n                    <scp>MCL<\/scp>\n                    \u20101 and\n                    <scp>MAPK<\/scp>\n                    overcomes venetoclax resistance in\n                    <scp>FLT3<\/scp>\n                    \u2010\n                    <scp>ITD\u2010<\/scp>\n                    positive\n                    <scp>AML<\/scp>\n                    cells harbouring activating\n                    <scp>PTPN11<\/scp>\n                    (\n                    <scp>SHP<\/scp>\n                    \u20102) mutations"],"prefix":"10.1111","volume":"208","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2423-3237","authenticated-orcid":false,"given":"Maximilian","family":"Fleischmann","sequence":"first","affiliation":[{"name":"Department of Hematology and Medical Oncology, Clinic for Internal Medicine II, Comprehensive Cancer Center Central Germany\u2014Campus Jena University Hospital Jena  Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Clinic for Internal Medicine II, Comprehensive Cancer Center Central Germany\u2014Campus Jena University Hospital Jena  Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Voigtl\u00e4nder","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Clinic for Internal Medicine II, Comprehensive Cancer Center Central Germany\u2014Campus Jena University Hospital Jena  Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Bechwar","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Clinic for Internal Medicine II, Comprehensive Cancer Center Central Germany\u2014Campus Jena University Hospital Jena  Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenny\u2010Joseph","family":"Schwietzer","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Clinic for Internal Medicine II, Comprehensive Cancer Center Central Germany\u2014Campus Jena University Hospital Jena  Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanja","family":"Bahr","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Clinic for Internal Medicine II, Comprehensive Cancer Center Central Germany\u2014Campus Jena University Hospital Jena  Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7455-8988","authenticated-orcid":false,"given":"Ulf","family":"Schnetzke","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Clinic for Internal Medicine II, Comprehensive Cancer Center Central Germany\u2014Campus Jena University Hospital Jena  Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Hospital Jena  Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian H.","family":"Heidel","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation Hannover Medical School (MHH)  Hannover Germany"},{"name":"Leibniz Institute on Aging\u2014Fritz\u2010Lipmann\u2010Institute  Jena 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