REL01 | Tp53 in myeloid neoplasms

The TP53 gene encodes the transcription factor p53, a central regulator of genomic integrity and stem-cell fitness. Loss of TP53 function, through genetic mutations and/or deletion of chromosome 17, disrupts DNA damage checkpoints, promotes tolerance to genotoxic stress, and represents a key prognostic factor in myeloid neoplasms (MN). Across MN phenotypes, TP53-driven diseases (most commonly therapy-related neoplasms and myelodysplastic syndromes (MDS) are characterized by an aggressive clinical course and high-risk chromosomal aberrations 1. In acute myeloid leukemia (AML) and MDS, TP53 mutations define one of the most adverse-risk biological subsets, associated with primary chemoresistance or only transient responses to hypomethylating agents and very poor overall survival 1-3. Accordingly, contemporary classification systems recognize TP53 alterations as a distinct disease entity or molecular category 4-5. Despite these biological underpinnings, from a clinical perspective, TP53-mutated AML/MDS remain an urgent unmet medical need, as no current or investigational therapy consistently achieves durable disease control or long-term survival 1(Table 1). Mechanistic dissection of TP53-driven leukemogenesis has recently highlighted the critical role of allelic state. Experimental in vitro and in vivo models show that monoallelic TP53 alterations confer selective clonal fitness under cytotoxic or radiation-induced stress with relatively limited genomic instability, whereas biallelic inactivation leads to defective p53 signaling, large-scale copy-number alterations, and acquisition of autonomous self-renewal culminating in leukemic transformation 6. Despite these biological insights, the clinical implications of TP53 biallelic status remain a matter of debate 7-9. Consistent with these mechanisms, TP53 mutations also confer adverse prognosis in myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. In chronic myelomonocytic leukemia (CMML), TP53 alterations are among the strongest predictors of inferior survival and leukemic transformation 10, while in MDS/MPN not otherwise specified (NOS) they define a biologically distinct high-risk molecular subtype 11. Beyond acute phenotypes, TP53 mutations adversely affect outcomes in (MPN), including essential thrombocythemia and myelofibrosis 12-13. Recent data suggest a context-dependent effect in MPN, where male sex, multi-hit status, absence of transplantation, and advanced versus chronic disease phase predict worse outcomes, findings further confirmed in the transplantation setting. Collectively, TP53 alterations represent a high-risk biological feature across myeloid neoplasm phenotypes. Further studies are required to clarify the leukemogenic processes driven by TP53 dysfunction and to develop effective disease-modifying therapeutic strategies for this critical unmet clinical need. References: 1Daver NG, Maiti A, Kadia TM, Vyas P, Majeti R, Wei AH, Garcia-Manero G, Craddock C, Sallman DA, Kantarjian HM. TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions. Cancer Discov. 2022 Nov 2;12(11):2516-2529. doi: 10.1158/2159-8290.CD-22-0332. Erratum in: Cancer Discov. 2022 Dec 2;12(12):2954. 2Bories P, Prade N, Lagarde S, Cabarrou B, Largeaud L, Plenecassagnes J, Luquet I, De Mas V, Filleron T, Cassou M, Sarry A, Fornecker LM, Simand C, Bertoli S, Recher C, Delabesse E. Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine. PLoS One. 2020 Oct 1;15(10):e0238795. 3Takahashi K, Patel K, Bueso-Ramos C, Zhang J, Gumbs C, Jabbour E, Kadia T, Andreff M, Konopleva M, DiNardo C, Daver N, Cortes J, Estrov Z, Futreal A, Kantarjian H, Garcia-Manero G. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents. 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Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020 Oct;26(10):1549-1556. doi: 10.1038/s41591-020-1008-z. Epub 2020 Aug 3. Erratum in: Nat Med. 2021 Mar;27(3):562. doi: 10.1038/s41591-021-01253-5. 9Grob T, Al Hinai ASA, Sanders MA, Kavelaars FG, Rijken M, Gradowska PL, Biemond BJ, Breems DA, Maertens J, van Marwijk Kooy M, Pabst T, de Weerdt O, Ossenkoppele GJ, van de Loosdrecht AA, Huls GA, Cornelissen JJ, Beverloo HB, Löwenberg B, Jongen-Lavrencic M, Valk PJM. Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome. 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TP53 Mutations in Myeloproli