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000304438 0247_ $$2doi$$a10.1182/blood.2024026113
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000304438 041__ $$aEnglish
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000304438 1001_ $$00009-0001-1925-3441$$aDamaskou, Aristi$$b0
000304438 245__ $$aPosttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in NPM1-mutant AML.
000304438 260__ $$aWashington, DC$$bAmerican Society of Hematology$$c2025
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000304438 520__ $$aNPM1 is a multifunctional phosphoprotein with key roles in ribosome biogenesis among its many functions. NPM1 gene mutations drive 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal and create a novel nuclear export signal, leading to cytoplasmic displacement of the protein (NPM1c). NPM1c mutations prime hematopoietic progenitors to leukemic transformation, but their precise molecular consequences remain elusive. Here, we first evaluate the effects of isolated NPM1c mutations on the global proteome of preleukemic hematopoietic stem and progenitor cells (HSPCs) using conditional knockin Npm1cA/+ mice. We discover that many proteins involved in ribosome biogenesis are significantly depleted in these murine HSPCs, but also importantly in human NPM1-mutant AMLs. In line with this, we found that preleukemic Npm1cA/+ HSPCs display higher sensitivity to RNA polymerase I inhibitors, including actinomycin D (ActD), compared with Npm1+/+ cells. Combination treatment with ActD and venetoclax inhibited the growth and colony-forming ability of preleukemic and leukemic NPM1c+ cells, whereas low-dose ActD treatment was able to resensitize resistant NPM1c+ cells to venetoclax. Furthermore, using data from CRISPR dropout screens, we identified and validated TSR3, a 40S ribosomal maturation factor whose knockout preferentially inhibited the proliferation of NPM1c+ AML cells by activating a p53-dependent apoptotic response. Similarly, to low-dose ActD treatment, TSR3 depletion could partially restore sensitivity to venetoclax in therapy-resistant NPM1c+ AML models. Our findings propose that targeted disruption of ribosome biogenesis should be explored as a therapeutic strategy against NPM1-mutant AML.
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000304438 650_7 $$0117896-08-9$$2NLM Chemicals$$aNucleophosmin
000304438 650_7 $$2NLM Chemicals$$aNpm1 protein, mouse
000304438 650_7 $$2NLM Chemicals$$aNuclear Proteins
000304438 650_7 $$2NLM Chemicals$$aNPM1 protein, human
000304438 650_7 $$0N54AIC43PW$$2NLM Chemicals$$avenetoclax
000304438 650_7 $$2NLM Chemicals$$aBridged Bicyclo Compounds, Heterocyclic
000304438 650_7 $$2NLM Chemicals$$aSulfonamides
000304438 650_7 $$01CC1JFE158$$2NLM Chemicals$$aDactinomycin
000304438 650_2 $$2MeSH$$aNucleophosmin
000304438 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: genetics
000304438 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: drug therapy
000304438 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: pathology
000304438 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: metabolism
000304438 650_2 $$2MeSH$$aAnimals
000304438 650_2 $$2MeSH$$aNuclear Proteins: genetics
000304438 650_2 $$2MeSH$$aNuclear Proteins: metabolism
000304438 650_2 $$2MeSH$$aMice
000304438 650_2 $$2MeSH$$aHumans
000304438 650_2 $$2MeSH$$aRibosomes: metabolism
000304438 650_2 $$2MeSH$$aRibosomes: genetics
000304438 650_2 $$2MeSH$$aMutation
000304438 650_2 $$2MeSH$$aBridged Bicyclo Compounds, Heterocyclic: pharmacology
000304438 650_2 $$2MeSH$$aSulfonamides: pharmacology
000304438 650_2 $$2MeSH$$aHematopoietic Stem Cells: metabolism
000304438 650_2 $$2MeSH$$aHematopoietic Stem Cells: pathology
000304438 650_2 $$2MeSH$$aDactinomycin: pharmacology
000304438 7001_ $$00000-0001-5129-7295$$aWilson, Rachael$$b1
000304438 7001_ $$00000-0002-3134-1276$$aGozdecka, Malgorzata$$b2
000304438 7001_ $$00000-0003-1390-6592$$aGiotopoulos, George$$b3
000304438 7001_ $$00000-0001-5077-3798$$aAsby, Ryan$$b4
000304438 7001_ $$00000-0002-1842-5838$$aEleftheriou, Maria$$b5
000304438 7001_ $$aGu, Muxin$$b6
000304438 7001_ $$00000-0002-3332-4525$$aRécher, Christian$$b7
000304438 7001_ $$00000-0003-1878-9129$$aMansat-De Mas, Véronique$$b8
000304438 7001_ $$00000-0002-0063-4404$$aVergez, Francois$$b9
000304438 7001_ $$00000-0003-4755-2884$$aSahal, Ambrine$$b10
000304438 7001_ $$0P:(DE-He78)4a70d3cfc2a9c4739cd4e53bfae885e7$$aVick, Binje$$b11
000304438 7001_ $$aPapachristou, Evangelia K$$b12
000304438 7001_ $$00000-0002-2985-5059$$aSawle, Ashley$$b13
000304438 7001_ $$00000-0003-2913-0012$$aYankova, Eliza$$b14
000304438 7001_ $$aDudek, Monika$$b15
000304438 7001_ $$aLiu, Xiaoxuan$$b16
000304438 7001_ $$00000-0002-9431-8428$$aRussell, James$$b17
000304438 7001_ $$aRak, Justyna$$b18
000304438 7001_ $$00000-0002-9596-7833$$aHilcenko, Christine$$b19
000304438 7001_ $$aD'Santos, Clive$$b20
000304438 7001_ $$0P:(DE-He78)0dc58a3349e4e66a46410a2067e43828$$aJeremias, Irmela$$b21$$udkfz
000304438 7001_ $$00000-0002-6704-2032$$aSarry, Jean-Emmanuel$$b22
000304438 7001_ $$00000-0002-4865-7648$$aTzelepis, Konstantinos$$b23
000304438 7001_ $$00000-0003-0312-161X$$aHuntly, Brian J P$$b24
000304438 7001_ $$00000-0001-9277-4553$$aWarren, Alan J$$b25
000304438 7001_ $$aTavana, Omid$$b26
000304438 7001_ $$00000-0003-4337-8022$$aVassiliou, George S$$b27
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