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000282691 1001_ $$aRein, Avigail$$b0
000282691 245__ $$aCellular and metabolic characteristics of pre-leukemic hematopoietic progenitors with GATA2 haploinsufficiency.
000282691 260__ $$aPavia$$bFerrata Storti Foundation$$c2023
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000282691 520__ $$aMono-allelic germline disruptions of the transcription factor GATA2 result in a propensity for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), affecting more than 85% of carriers. How a partial loss of GATA2 functionality enables leukemic transformation years later is unclear. This question has remained unsolved mainly due to the lack of informative models, as Gata2 heterozygote mice do not develop hematologic malignancies. Here we show that two different germline Gata2 mutations (TgErg/Gata2het and TgErg/Gata2L359V) accelerate AML in mice expressing the human hematopoietic stem cell regulator ERG. Analysis of Erg/Gata2het fetal liver and bone marrow-derived hematopoietic cells revealed a distinct pre-leukemic phenotype. This was characterized by enhanced transition from stem to progenitor state, increased proliferation, and a striking mitochondrial phenotype, consisting of highly expressed oxidative-phosphorylation-related gene sets, elevated oxygen consumption rates, and notably, markedly distorted mitochondrial morphology. Importantly, the same mitochondrial gene-expression signature was observed in human AML harboring GATA2 aberrations. Similar to the observations in mice, non-leukemic bone marrows from children with germline GATA2 mutation demonstrated marked mitochondrial abnormalities. Thus, we observed the tumor suppressive effects of GATA2 in two germline Gata2 genetic mouse models. As oncogenic mutations often accumulate with age, GATA2 deficiency-mediated priming of hematopoietic cells for oncogenic transformation may explain the earlier occurrence of MDS/AML in patients with GATA2 germline mutation. The mitochondrial phenotype is a potential therapeutic opportunity for the prevention of leukemic transformation in these patients.
000282691 536__ $$0G:(DE-HGF)POF4-311$$a311 - Zellbiologie und Tumorbiologie (POF4-311)$$cPOF4-311$$fPOF IV$$x0
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000282691 650_7 $$2NLM Chemicals$$aGATA2 Transcription Factor
000282691 650_7 $$2NLM Chemicals$$aGATA2 protein, human
000282691 650_2 $$2MeSH$$aChild
000282691 650_2 $$2MeSH$$aHumans
000282691 650_2 $$2MeSH$$aMice
000282691 650_2 $$2MeSH$$aAnimals
000282691 650_2 $$2MeSH$$aGATA2 Deficiency: genetics
000282691 650_2 $$2MeSH$$aMyelodysplastic Syndromes: pathology
000282691 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: genetics
000282691 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: metabolism
000282691 650_2 $$2MeSH$$aBone Marrow: pathology
000282691 650_2 $$2MeSH$$aHematopoietic Stem Cells: metabolism
000282691 650_2 $$2MeSH$$aCell Transformation, Neoplastic: genetics
000282691 650_2 $$2MeSH$$aCell Transformation, Neoplastic: metabolism
000282691 650_2 $$2MeSH$$aGATA2 Transcription Factor: genetics
000282691 650_2 $$2MeSH$$aGATA2 Transcription Factor: metabolism
000282691 7001_ $$aGeron, Ifat$$b1
000282691 7001_ $$aKugler, Eitan$$b2
000282691 7001_ $$aFishman, Hila$$b3
000282691 7001_ $$aGottlieb, Eyal$$b4
000282691 7001_ $$aAbramovich, Ifat$$b5
000282691 7001_ $$aGiladi, Amir$$b6
000282691 7001_ $$aAmit, Ido$$b7
000282691 7001_ $$aMulet-Lazaro, Roger$$b8
000282691 7001_ $$aDelwel, Ruud$$b9
000282691 7001_ $$0P:(DE-He78)5120a331b1c28045c8ca6a8b1c73c95f$$aGröschel, Stefan$$b10
000282691 7001_ $$aLevin-Zaidman, Smadar$$b11
000282691 7001_ $$aDezorella, Nili$$b12
000282691 7001_ $$aHoldengreber, Vered$$b13
000282691 7001_ $$aRao, Tata Nageswara$$b14
000282691 7001_ $$aYacobovich, Joanne$$b15
000282691 7001_ $$aSteinberg-Shemer, Orna$$b16
000282691 7001_ $$aHuang, Qiu-Hua$$b17
000282691 7001_ $$aTan, Yun$$b18
000282691 7001_ $$aChen, Sai-Juan$$b19
000282691 7001_ $$aIzraeli, Shai$$b20
000282691 7001_ $$aBirger, Yehudit$$b21
000282691 773__ $$0PERI:(DE-600)2805244-4$$a10.3324/haematol.2022.279437$$gVol. 108, no. 9$$n9$$p2316-2330$$tHaematologica$$v108$$x0390-6078$$y2023
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