Tefferi, A.Abdelmagid, M.Loscocco, G.G.Fathima, S.Begna, K.H.Al-Kali, A.Foran, J.Palmer, J.Badar, T.Patnaik, M.M.Reichard, K.K.He, R.Zepeda Mendoza, C.J.Shah, M.Orazi, A.Arber, D.A.Pardanani, A.Vannucchi, A.M.Hiwase, D.Gangat, N.et al.2025-07-162025-07-162025American Journal of Hematology, 2025; 100(4):552-5600361-86091096-8652https://hdl.handle.net/2440/145994The clinical relevance of TP53 mutations (TP53 MUT ) in myeloproliferative neoplasms (MPN) and their prognostic interaction with MPN subtype designation has not been systematically studied. In the current study, 114 patients with MPN harboring TP53 MUT (VAF ≥ 2%) were evaluated for overall survival (OS), calculated from the time of TP53 MUT detection: chronic phase myelofibrosis (MF-CP; N = 61); blast-phase (MPN-BP; N = 31) or accelerated-phase (MPN-AP; N = 16) MPN, and polycythemia vera/essential thrombocythemia (PV/ET; N = 6). Sixty-five (57%) patients harbored International Consensus Classification (ICC)-defined multihit TP53 MUT and 56 (49%) monosomal/complex karyotype (MK/CK). Majority of MPN-BP (90%) and MPN-AP (81%) while 39% of MF-CP and none of PV/ET patients harbored multihit TP53 MUT . OS in MPN-BP and MPN-AP was equally dismal (median 6 vs. 4.5 months, respectively; p = 1.0), regardless of multihit configuration (p = 0.44), while OS in TP53 MUT MPN-BP/AP (N = 47; median 4 months) was inferior to that of a separate cohort (N = 49) with TP53 wild-type MPN-BP/AP (median 11 months; p < 0.01). OS in MF-CP was significantly shorter with multihit versus non-multihit TP53 MUT (median 10 vs. 35 months; HR 2.9; p < 0.01), independent of other MF-relevant genetic risk factors, including ASXL1/SRSF2/U2AF1 mutations. Multihit TP53 MUT was also associated with inferior survival following allogeneic stem cell transplant (ASCT): median 9 months versus “not reached” in patients with (N = 9) versus without (N = 8) multihit TP53 MUT (p < 0.01). The presence of multihit or non-multihit TP53 MUT in MPN-BP/AP or multihit TP53 MUT in MF-CP is associated with exceptionally poor prognosis and justifies inclusion into the ICC category of “myeloid neoplasms with mutated TP53.” By contrast, detection of non-multihit TP53 MUT, by itself, might not endanger short-term survival in MF-CP, PV, or ET.en© 2025 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.ICCkaryotypeprognosissurvivalWHOHumansMyeloproliferative DisordersPrognosisMutationAdultAgedAged, 80 and overMiddle AgedFemaleMaleTumor Suppressor Protein p53Journal article10.1002/ajh.27609728115Hiwase, D. [0000-0002-6666-3056]