In vitro tests allowing to identify the potential for mdm2 inhibitors to induce the selection of mutations in patients suffering from a myeloproliferative neoplasm

TP53 mutations are the most frequent mutations in all cancer subtypes and their acquisition are key events leading to the transformation of chronic myeloproliferative neoplasms (MPN) to leukemia. The MDM2 ubiquitin ligase is responsible for proteasome-dependent p53 degradation. MDM2 inhibitors (nutlins) may rescue p53 from degradation and have been evaluated in a variety of cancers. The inventors report herein evidence of a direct effect of MDM2 inhibition on the selection of MPN patients’ cells harboring TP53 mutations. To decipher whether these mutations can arise in a specific molecular context they used a DNA single cell approach to determine the clonal architecture of TP53 mutations. They observed that: (i) clonal evolution in MPN frequently consists of sequential branching instead of linear consecutive acquisition of mutations in the same clone; (ii) TP53 mutations are late events mainly occurring in the driver clone; (iii) additional mutations don’t appear to influence the selection by MDM2 inhibitor treatment. This is the first demonstration that a treatment can directly favor the emergence of potentially aggressive MPN subclones. As the molecular environment doesn’t affect the potential selection of TP53 mutated cells by MDM2 inhibitors, such events could occur irrespective of the subtype of cancer.

Keywords: myeloproliferative neoplasm (MPN), TP53-mutation, MDM2 inhibitor, treatment response prediction
Patent Application number: EP21 305 499.2 on 15/04/2021 and PCT/EP2022/060039 on 14/04/2022
Blood Adv 2022 May 10 Maslah et al. Single-cell analysis reveals selection of TP53-mutated clones after MDM2 inhibition doi: 10.1182/bloodadvances.2021005867.

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