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000298222 1001_ $$0P:(DE-He78)1875dd3a72033b3b8b5b55d10c6229dd$$aArseni, Lavinia$$b0$$eFirst author$$udkfz
000298222 245__ $$aLongitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL.
000298222 260__ $$a[London]$$bSpringer Nature$$c2025
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000298222 520__ $$aChronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment response, relapse under therapy occurrs with an aggressive outgrowth of malignant cells, resembling observations in patients. A comparative analysis of exome, transcriptome and proteome of sorted leukemic murine cells during treatment and after relapse suggests alterations in the proteasome activity as a driver of ibrutinib resistance. Preclinical treatment with the irreversible proteasome inhibitor carfilzomib administered upon ibrutinib resistance prolongs survival of mice. Longitudinal proteomic analysis of ibrutinib-resistant patients identifies deregulation in protein post-translational modifications. Additionally, cells from ibrutinib-resistant patients effectively respond to several proteasome inhibitors in co-culture assays. Altogether, our results from orthogonal omics approaches identify proteasome inhibition as potentially attractive treatment for chronic lymphocytic leukemia patients resistant or refractory to ibrutinib.
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000298222 650_7 $$01X70OSD4VX$$2NLM Chemicals$$aibrutinib
000298222 650_7 $$072X6E3J5AR$$2NLM Chemicals$$acarfilzomib
000298222 650_7 $$0JAC85A2161$$2NLM Chemicals$$aAdenine
000298222 650_7 $$2NLM Chemicals$$aPiperidines
000298222 650_7 $$2NLM Chemicals$$aProteasome Inhibitors
000298222 650_7 $$2NLM Chemicals$$aOligopeptides
000298222 650_7 $$2NLM Chemicals$$aPyrimidines
000298222 650_7 $$2NLM Chemicals$$aPyrazoles
000298222 650_7 $$0EC 3.4.25.1$$2NLM Chemicals$$aProteasome Endopeptidase Complex
000298222 650_2 $$2MeSH$$aAdenine: analogs & derivatives
000298222 650_2 $$2MeSH$$aAdenine: therapeutic use
000298222 650_2 $$2MeSH$$aAdenine: pharmacology
000298222 650_2 $$2MeSH$$aLeukemia, Lymphocytic, Chronic, B-Cell: drug therapy
000298222 650_2 $$2MeSH$$aLeukemia, Lymphocytic, Chronic, B-Cell: genetics
000298222 650_2 $$2MeSH$$aLeukemia, Lymphocytic, Chronic, B-Cell: metabolism
000298222 650_2 $$2MeSH$$aPiperidines: pharmacology
000298222 650_2 $$2MeSH$$aPiperidines: therapeutic use
000298222 650_2 $$2MeSH$$aAnimals
000298222 650_2 $$2MeSH$$aHumans
000298222 650_2 $$2MeSH$$aProteasome Inhibitors: pharmacology
000298222 650_2 $$2MeSH$$aProteasome Inhibitors: therapeutic use
000298222 650_2 $$2MeSH$$aDrug Resistance, Neoplasm: genetics
000298222 650_2 $$2MeSH$$aDrug Resistance, Neoplasm: drug effects
000298222 650_2 $$2MeSH$$aOligopeptides: pharmacology
000298222 650_2 $$2MeSH$$aOligopeptides: therapeutic use
000298222 650_2 $$2MeSH$$aMice
000298222 650_2 $$2MeSH$$aPyrimidines: pharmacology
000298222 650_2 $$2MeSH$$aPyrimidines: therapeutic use
000298222 650_2 $$2MeSH$$aPyrazoles: pharmacology
000298222 650_2 $$2MeSH$$aPyrazoles: therapeutic use
000298222 650_2 $$2MeSH$$aProteomics
000298222 650_2 $$2MeSH$$aProteasome Endopeptidase Complex: metabolism
000298222 650_2 $$2MeSH$$aDisease Models, Animal
000298222 650_2 $$2MeSH$$aFemale
000298222 650_2 $$2MeSH$$aCell Line, Tumor
000298222 7001_ $$0P:(DE-He78)a63bd9276ca497fcfcd476478727a6dc$$aSigismondo, Gianluca$$b1$$eFirst author$$udkfz
000298222 7001_ $$0P:(DE-He78)a2b772a0a0db4a79b24771b8497dd9bd$$aYazdanparast, Haniyeh$$b2
000298222 7001_ $$00000-0003-3830-2277$$aHermansen, Johanne U$$b3
000298222 7001_ $$0P:(DE-He78)e73a0a4fab40344d89d693cbe1df3109$$aMack, Norman$$b4$$udkfz
000298222 7001_ $$0P:(DE-He78)5ad7de84a84805746cf4d7f7f90cdbff$$aOhl, Sibylle$$b5$$udkfz
000298222 7001_ $$0P:(DE-He78)ece9c40a97e047bf607a89f04fcc7466$$aKalter, Verena$$b6$$udkfz
000298222 7001_ $$0P:(DE-He78)f28fcc92d5c00f3ee511e3319c699b38$$aIskar, Murat$$b7
000298222 7001_ $$aKalxdorf, Mathias$$b8
000298222 7001_ $$0P:(DE-He78)263d95a5b6ba4abce7abee7185b9630e$$aFriedel, Dennis$$b9$$udkfz
000298222 7001_ $$00000-0002-8304-3385$$aRettel, Mandy$$b10
000298222 7001_ $$0P:(DE-He78)1cd5686a9bcef9182c18a1cb799637d3$$aPaul, Yashna$$b11
000298222 7001_ $$aRingshausen, Ingo$$b12
000298222 7001_ $$00000-0003-0561-6640$$aEldering, Eric$$b13
000298222 7001_ $$aDubois, Julie$$b14
000298222 7001_ $$00000-0003-3190-1891$$aKater, Arnon P$$b15
000298222 7001_ $$0P:(DE-He78)1beba8f953e7ae7e96e8d3e9a48f10f7$$aZapatka, Marc$$b16$$udkfz
000298222 7001_ $$0P:(DE-HGF)0$$aRoessner, Philipp M$$b17
000298222 7001_ $$aTausch, Eugen$$b18
000298222 7001_ $$00000-0002-6830-9296$$aStilgenbauer, Stephan$$b19
000298222 7001_ $$aDietrich, Sascha$$b20
000298222 7001_ $$00000-0003-2011-9247$$aSavitski, Mikhail M$$b21
000298222 7001_ $$00000-0003-1630-356X$$aSkånland, Sigrid S$$b22
000298222 7001_ $$0P:(DE-He78)939d5891259c638c1ab053b1456a578c$$aKrijgsveld, Jeroen$$b23$$udkfz
000298222 7001_ $$0P:(DE-He78)e13b4363c5fe858044ef8a39c02c870c$$aLichter, Peter$$b24$$udkfz
000298222 7001_ $$0P:(DE-He78)e67f907703fcb2cf909f4d72d50268b5$$aSeiffert, Martina$$b25$$eLast author$$udkfz
000298222 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-025-56318-7$$gVol. 16, no. 1, p. 1041$$n1$$p1041$$tNature Communications$$v16$$x2041-1723$$y2025
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