Higher MDMX expression was associated with hypomethylating agent resistance and inferior survival in MDS patients, inferring it a potential therapeutic target

Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International consensus classification of myeloid neoplasms and acute leukemia: integrating morphological, clinical, and genomic data. Blood. 2022;140:1200–28.

Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36:1703–19.

Article  PubMed  PubMed Central  Google Scholar 

Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Haase D, Stevenson KE, Neuberg D, Maciejewski JP, Nazha A, Sekeres MA, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019;33:1747–58.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Carvajal LA, Neriah DB, Senecal A, Benard L, Thiruthuvanathan V, Yatsenko T, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med. 2018;10:eaao3003.

Ueda K, Kumari R, Schwenger E, Wheat JC, Bohorquez O, Narayanagari SR, et al. MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism. Cancer Cell. 2021;39:529–47.e7.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schimmer RR, Kovtonyuk LV, Klemm N, Fullin J, Stolz SM, Mueller J, et al. TP53 mutations confer resistance to hypomethylating agents and BCL-2 inhibition in myeloid neoplasms. Blood Adv. 2022;6:3201–6.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Komrokji RS, Sallman DA, Al Ali N, Padron E, Sweet K, Lancet JE, et al. Outcome of myelodysplastic syndrome patients with TP53 mutation treated with hypomethylating agents. Blood. 2017;130:1687.

Google Scholar 

Stomper J, Rotondo JC, Greve G, Lübbert M. Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies. Leukemia. 2021;35:1873–89.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Itzykson R, Thépot S, Quesnel B, Dreyfus F, Beyne-Rauzy O, Turlure P, et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117:403–11.

Article  CAS  PubMed  Google Scholar 

Bejar R, Lord A, Stevenson K, Bar-Natan M, Pérez-Ladaga A, Zaneveld J, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014;124:2705–12.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lee EJ, Zeidan AM. Genome sequencing in myelodysplastic syndromes: can molecular mutations predict benefit from hypomethylating agent therapy? Expert Rev Hematol. 2015;8:155–8.

Article  CAS  PubMed  Google Scholar 

Daver NG, Maiti A, Kadia TM, Vyas P, Majeti R, Wei AH, et al. TP53-mutated myelodysplastic syndrome and acute myeloid leukemia: biology, current therapy, and future directions. Cancer Discov. 2022;12:2516–29.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Adès L, Girshova L, Doronin VA, Díez-Campelo M, Valcárcel D, Kambhampati S, et al. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML. Blood Adv. 2022;6:5132–45.

Article  PubMed  PubMed Central  Google Scholar 

Gilead To Discontinue Phase 3 ENHANCE study of magrolimab plus azacitidine in higher-risk MDS [press release]. July 2023.

Comments (0)

No login
gif