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@ARTICLE{Sidorova:179089,
      author       = {O. A. Sidorova and S. Sayed and M. Paszkowski-Rogacz and M.
                      Seifert and A. Camgöz$^*$ and I. Roeder and M.
                      Bornhäuser$^*$ and C. Thiede$^*$ and F. Buchholz$^*$},
      title        = {{RNA}i-{M}ediated {S}creen of {P}rimary {AML} {C}ells
                      {N}ominates {MDM}4 as a {T}herapeutic {T}arget in {NK}-{AML}
                      with {DNMT}3{A} {M}utations.},
      journal      = {Cells},
      volume       = {11},
      number       = {5},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2022-00454},
      pages        = {854},
      year         = {2022},
      abstract     = {DNA-methyltransferase 3A (DNMT3A) 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
                      DNMT3A-driven AML cells, we have performed a focused RNAi
                      screen in a panel of 30 primary AML samples, all carrying a
                      DNMT3A R882 mutation. As one of the strongest hits, we
                      identified MDM4 as a gene essential for proliferation of
                      primary DNMT3AWT/R882X 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 DNMT3A-mutant samples.
                      Moreover, we found that the MDM2/4 inhibitor ALRN-6924
                      impairs growth of DNMT3AWT/R882X 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 DNMT3A R882X
                      mutations.},
      keywords     = {DNMT3A (Other) / MDM4 (Other) / RNAi (Other) / acute
                      myeloid leukemia (Other) / functional screen (Other)},
      cin          = {B062 / DD01},
      ddc          = {570},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)DD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35269477},
      pmc          = {pmc:PMC8909053},
      doi          = {10.3390/cells11050854},
      url          = {https://inrepo02.dkfz.de/record/179089},
}