RNAi-Mediated Screen of Primary AML Cells Nominates MDM4 as a Therapeutic Target in NK-AML with DNMT3A Mutations

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 5; p. 854
• Main Authors: Sidorova, Olga Alexandra, Sayed, Shady, Paszkowski-Rogacz, Maciej, Seifert, Michael, Camgöz, Aylin, Roeder, Ingo, Bornhäuser, Martin, Thiede, Christian, Buchholz, Frank
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 02.03.2022; MDPI
• Subjects: Acute myeloid leukemia; Adult; Cancer; Cell culture; Cell cycle; Cell Cycle Proteins - metabolism; Cell proliferation; Chemotherapy; Cytokines; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA methyltransferase; DNA Methyltransferase 3A; DNMT3A; Epigenetics; Flow cytometry; functional screen; Humans; Infections; Karyotypes; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemogenesis; Lymphocytes; MDM2 protein; MDM4; Medical prognosis; Mutants; Mutation; Mutation - genetics; p53 Protein; Patients; Progenitor cells; Proto-Oncogene Proteins - metabolism; RNA Interference; RNA-mediated interference; RNAi; Stem cells; Therapeutic targets; Transcription; Canada; St Louis Missouri; United States > US; Berlin Germany; Germany; RNAi; MDM4; functional screen; acute myeloid leukemia; DNMT3A
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11050854

( ) mutations belong to the most frequent genetic aberrations found in adult acute myeloid leukemia (AML). Recent evidence suggests that these mutations arise early in leukemogenesis, marking leukemic progenitors and stem cells, and persist through consolidation chemotherapy, providing a pool for AML relapse. Currently, there are no therapeutic approaches directed specifically against this cell population. To unravel therapeutically actionable targets in mutant -driven AML cells, we have performed a focused RNAi screen in a panel of 30 primary AML samples, all carrying a R882 mutation. As one of the strongest hits, we identified as a gene essential for proliferation of primary AML cells. We analyzed a publicly available RNA-Seq dataset of primary normal karyotype (NK) AML samples and found a trend towards MDM4 transcript overexpression particularly in -mutant samples. Moreover, we found that the MDM2/4 inhibitor ALRN-6924 impairs growth of primary cells in vitro by inducing cell cycle arrest through upregulation of p53 target genes. Our results suggest that MDM4 inhibition is a potential target in NK-AML patients bearing R882X mutations.