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. 2022 Dec 22.
doi: 10.1111/bjh.18608. Online ahead of print.

Reduced murine double minute 2 and 4 protein, but not messenger RNA, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia

Norman Salomao  1 , Nabih Maslah  1 , Anouk Giulianelli  2 , Louis Drevon  1   2 , Lorea Aguinaga  1   2 , Xiaolian Gu  3 , Bruno Cassinat  1   2 , Stephane Giraudier  1   2 , Pierre Fenaux  2 , Robin Fahraeus  1   3   4
Affiliations

Reduced murine double minute 2 and 4 protein, but not messenger RNA, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia

Norman Salomao et al. Br J Haematol. .

Abstract

The human homologues of murine double minute 2 (MDM2) and 4 (MDM4) negatively regulate p53 tumour suppressor activity and are reported to be frequently overexpressed in human malignancies, prompting clinical trials with drugs that prevent interactions between MDM2/MDM4 and p53. Bone marrow samples from 111 patients with acute myeloblastic leukaemia, myelodysplastic syndrome or chronic myelomonocytic leukaemia were examined for protein (fluorescence-activated cell sorting) and messenger RNA (mRNA) expression (quantitative polymerase chain reaction) of MDM2, MDM4 and tumour protein p53 (TP53). Low protein expression of MDM2 and MDM4 was observed in immature cells from patients with excess of marrow blasts (>5%) compared with CD34+ /CD45low cells from healthy donors and patients without excess of marrow blasts (<5%). The mRNA levels were indistinguishable in all samples examined regardless of disease status or blast levels. Low MDM2 and MDM4 protein expression were correlated with poor survival. These data show a poor correlation between mRNA and protein expression levels, suggesting that quantitative flow cytometry analysis of protein expression levels should be used to predict and validate the efficacy of MDM2 and MDM4 inhibitors. These findings show that advanced disease is associated with reduced MDM2 and MDM4 protein expression and indicate that the utility of MDM2 and MDM4 inhibitors may have to be reconsidered in the treatment of advanced myeloid malignancies.

Keywords: acute myeloid leukaemia; murine double minute 2 (MDM2); murine double minute 4 (MDM4); myelodysplastic syndrome; p53.

References

REFERENCES

    1. Marcellino BK, Hoffman R, Tripodi J, Lu M, Kosiorek H, Mascarenhas J, et al. Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53. Blood Adv. 2018;2(24):3581-9.
    1. Nakatake M, Monte-Mor B, Debili N, Casadevall N, Ribrag V, Solary E, et al. JAK2(V617F) negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms. Oncogene. 2012;31(10):1323-33.
    1. Trotta R, Vignudelli T, Candini O, Intine RV, Pecorari L, Guerzoni C, et al. BCR/ABL activates mdm2 mRNA translation via the La antigen. Cancer Cell. 2003;3(2):145-60.
    1. Reis B, Jukofsky L, Chen G, Martinelli G, Zhong H, So WV, et al. Acute myeloid leukemia patients' clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts. Haematologica. 2016;101(5):e185-8.
    1. Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer févr. 2013;13(2):83-96.