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@ARTICLE{Rein:282691,
      author       = {A. Rein and I. Geron and E. Kugler and H. Fishman and E.
                      Gottlieb and I. Abramovich and A. Giladi and I. Amit and R.
                      Mulet-Lazaro and R. Delwel and S. Gröschel$^*$ and S.
                      Levin-Zaidman and N. Dezorella and V. Holdengreber and T. N.
                      Rao and J. Yacobovich and O. Steinberg-Shemer and Q.-H.
                      Huang and Y. Tan and S.-J. Chen and S. Izraeli and Y.
                      Birger},
      title        = {{C}ellular and metabolic characteristics of pre-leukemic
                      hematopoietic progenitors with {GATA}2 haploinsufficiency.},
      journal      = {Haematologica},
      volume       = {108},
      number       = {9},
      issn         = {0390-6078},
      address      = {Pavia},
      publisher    = {Ferrata Storti Foundation},
      reportid     = {DKFZ-2023-01837},
      pages        = {2316-2330},
      year         = {2023},
      abstract     = {Mono-allelic germline disruptions of the transcription
                      factor GATA2 result in a propensity for developing
                      myelodysplastic syndrome (MDS) and acute myeloid leukemia
                      (AML), affecting more than $85\%$ of carriers. How a partial
                      loss of GATA2 functionality enables leukemic transformation
                      years later is unclear. This question has remained unsolved
                      mainly due to the lack of informative models, as Gata2
                      heterozygote mice do not develop hematologic malignancies.
                      Here we show that two different germline Gata2 mutations
                      (TgErg/Gata2het and TgErg/Gata2L359V) accelerate AML in mice
                      expressing the human hematopoietic stem cell regulator ERG.
                      Analysis of Erg/Gata2het fetal liver and bone marrow-derived
                      hematopoietic cells revealed a distinct pre-leukemic
                      phenotype. This was characterized by enhanced transition
                      from stem to progenitor state, increased proliferation, and
                      a striking mitochondrial phenotype, consisting of highly
                      expressed oxidative-phosphorylation-related gene sets,
                      elevated oxygen consumption rates, and notably, markedly
                      distorted mitochondrial morphology. Importantly, the same
                      mitochondrial gene-expression signature was observed in
                      human AML harboring GATA2 aberrations. Similar to the
                      observations in mice, non-leukemic bone marrows from
                      children with germline GATA2 mutation demonstrated marked
                      mitochondrial abnormalities. Thus, we observed the tumor
                      suppressive effects of GATA2 in two germline Gata2 genetic
                      mouse models. As oncogenic mutations often accumulate with
                      age, GATA2 deficiency-mediated priming of hematopoietic
                      cells for oncogenic transformation may explain the earlier
                      occurrence of MDS/AML in patients with GATA2 germline
                      mutation. The mitochondrial phenotype is a potential
                      therapeutic opportunity for the prevention of leukemic
                      transformation in these patients.},
      keywords     = {Child / Humans / Mice / Animals / GATA2 Deficiency:
                      genetics / Myelodysplastic Syndromes: pathology / Leukemia,
                      Myeloid, Acute: genetics / Leukemia, Myeloid, Acute:
                      metabolism / Bone Marrow: pathology / Hematopoietic Stem
                      Cells: metabolism / Cell Transformation, Neoplastic:
                      genetics / Cell Transformation, Neoplastic: metabolism /
                      GATA2 Transcription Factor: genetics / GATA2 Transcription
                      Factor: metabolism / GATA2 Transcription Factor (NLM
                      Chemicals) / GATA2 protein, human (NLM Chemicals)},
      cin          = {A380},
      ddc          = {610},
      cid          = {I:(DE-He78)A380-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36475518},
      pmc          = {pmc:PMC10483369},
      doi          = {10.3324/haematol.2022.279437},
      url          = {https://inrepo02.dkfz.de/record/282691},
}