17 results on '"Skorski T"'
Search Results
2. Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells
- Author
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Skorski, T, primary, Kanakaraj, P, additional, Nieborowska-Skorska, M, additional, Ratajczak, MZ, additional, Wen, SC, additional, Zon, G, additional, Gewirtz, AM, additional, Perussia, B, additional, and Calabretta, B, additional more...
- Published
- 1995
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Catalog
3. DNA polymerase θ protects leukemia cells from metabolically induced DNA damage.
- Author
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Vekariya U, Toma M, Nieborowska-Skorska M, Le BV, Caron MC, Kukuyan AM, Sullivan-Reed K, Podszywalow-Bartnicka P, Chitrala KN, Atkins J, Drzewiecka M, Feng W, Chan J, Chatla S, Golovine K, Jelinek J, Sliwinski T, Ghosh J, Matlawska-Wasowska K, Chandramouly G, Nejati R, Wasik M, Sykes SM, Piwocka K, Hadzijusufovic E, Valent P, Pomerantz RT, Morton G, Childers W, Zhao H, Paietta EM, Levine RL, Tallman MS, Fernandez HF, Litzow MR, Gupta GP, Masson JY, and Skorski T more...
- Subjects
- Animals, Mice, BRCA2 Protein, DNA metabolism, DNA Polymerase theta, BRCA1 Protein, DNA Damage, Leukemia enzymology, Leukemia genetics
- Abstract
Leukemia cells accumulate DNA damage, but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/1-carbon cycle metabolism contributed to the accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases (OTKs: FLT3(internal tandem duplication [ITD]), JAK2(V617F), BCR-ABL1). To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLθ) via ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLθ and its proteasomal degradation. Overexpression of POLθ in OTK-positive cells resulted in the efficient repair of DPC-containing DNA double-strand breaks by POLθ-mediated end-joining. The transforming activities of OTKs and other leukemia-inducing oncogenes, especially of those causing the inhibition of BRCA1/2-mediated homologous recombination with and without concomitant inhibition of DNA-PK-dependent nonhomologous end-joining, was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLθ polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitors or DPC-inducing drug etoposide enhanced the antileukemia effect of POLθ inhibitor in vitro and in vivo. In conclusion, we demonstrated that POLθ plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde, and it can be targeted to achieve a therapeutic effect., (© 2023 by The American Society of Hematology.) more...
- Published
- 2023
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4. Tyrosine kinase inhibitor-induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors.
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Maifrede S, Nieborowska-Skorska M, Sullivan-Reed K, Dasgupta Y, Podszywalow-Bartnicka P, Le BV, Solecka M, Lian Z, Belyaeva EA, Nersesyan A, Machnicki MM, Toma M, Chatain N, Rydzanicz M, Zhao H, Jelinek J, Piwocka K, Sliwinski T, Stoklosa T, Ploski R, Fischer T, Sykes SM, Koschmieder S, Bullinger L, Valent P, Wasik MA, Huang J, and Skorski T more...
- Subjects
- Animals, BRCA1 Protein genetics, BRCA1 Protein metabolism, BRCA2 Protein genetics, BRCA2 Protein metabolism, Benzothiazoles pharmacology, Cell Line, Tumor, DNA Ligase ATP genetics, DNA Ligase ATP metabolism, Fanconi Anemia Complementation Group N Protein genetics, Fanconi Anemia Complementation Group N Protein metabolism, Humans, Mice, Mutation, Phenylurea Compounds pharmacology, Phthalazines pharmacology, Piperazines pharmacology, Poly (ADP-Ribose) Polymerase-1 genetics, Poly (ADP-Ribose) Polymerase-1 metabolism, Protein Kinase Inhibitors pharmacology, Rad51 Recombinase genetics, Rad51 Recombinase metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Xenograft Model Antitumor Assays, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Combined Chemotherapy Protocols pharmacology, DNA Repair drug effects, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 metabolism
- Abstract
Mutations in FMS-like tyrosine kinase 3 (FLT3), such as internal tandem duplications (ITDs), can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i's), which are rarely curative. PARP1 inhibitors (PARP1i's) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (HR) deficiency. We show here that inhibition of FLT3(ITD) activity by the FLT3i AC220 caused downregulation of DNA repair proteins BRCA1, BRCA2, PALB2, RAD51, and LIG4, resulting in inhibition of 2 major DNA double-strand break (DSB) repair pathways, HR, and nonhomologous end-joining. PARP1i, olaparib, and BMN673 caused accumulation of lethal DSBs and cell death in AC220-treated FLT3(ITD)-positive leukemia cells, thus mimicking synthetic lethality. Moreover, the combination of FLT3i and PARP1i eliminated FLT3(ITD)-positive quiescent and proliferating leukemia stem cells, as well as leukemic progenitors, from human and mouse leukemia samples. Notably, the combination of AC220 and BMN673 significantly delayed disease onset and effectively reduced leukemia-initiating cells in an FLT3(ITD)-positive primary AML xenograft mouse model. In conclusion, we postulate that FLT3i-induced deficiencies in DSB repair pathways sensitize FLT3(ITD)-positive AML cells to synthetic lethality triggered by PARP1i's. Therefore, FLT3(ITD) could be used as a precision medicine marker for identifying AML patients that may benefit from a therapeutic regimen combining FLT3 and PARP1i's., (© 2018 by The American Society of Hematology.) more...
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- 2018
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5. Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms.
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Nieborowska-Skorska M, Maifrede S, Dasgupta Y, Sullivan K, Flis S, Le BV, Solecka M, Belyaeva EA, Kubovcakova L, Nawrocki M, Kirschner M, Zhao H, Prchal JT, Piwocka K, Moliterno AR, Wasik M, Koschmieder S, Green TR, Skoda RC, and Skorski T more...
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- Animals, Calreticulin genetics, Cell Line, Drug Synergism, Heterografts, Humans, Janus Kinase 2 genetics, Mice, Myeloproliferative Disorders genetics, Neoplasms genetics, Nitriles, Phthalazines pharmacology, Piperazines pharmacology, Pyrimidines, Receptors, Thrombopoietin genetics, Tumor Cells, Cultured, DNA Repair drug effects, Myeloproliferative Disorders drug therapy, Neoplasms drug therapy, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Pyrazoles pharmacology
- Abstract
Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L), or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time, primary MPN cell samples from individual patients displayed a high degree of variability in sensitivity to these drugs. Ruxolitinib inhibited 2 major DSB repair mechanisms, BRCA-mediated homologous recombination and DNA-dependent protein kinase-mediated nonhomologous end-joining, and, when combined with olaparib, caused abundant accumulation of toxic DSBs resulting in enhanced elimination of MPN primary cells, including the disease-initiating cells from the majority of patients. Moreover, the combination of BMN673, ruxolitinib, and hydroxyurea was highly effective in vivo against JAK2(V617F)
+ murine MPN-like disease and also against JAK2(V617F)+ , CALR(del52)+ , and MPL(W515L)+ primary MPN xenografts. In conclusion, we postulate that ruxolitinib-induced deficiencies in DSB repair pathways sensitized MPN cells to synthetic lethality triggered by PARP inhibitors., (© 2017 by The American Society of Hematology.) more...- Published
- 2017
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6. Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases.
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Dasgupta Y, Koptyra M, Hoser G, Kantekure K, Roy D, Gornicka B, Nieborowska-Skorska M, Bolton-Gillespie E, Cerny-Reiterer S, Müschen M, Valent P, Wasik MA, Richardson C, Hantschel O, van der Kuip H, Stoklosa T, and Skorski T more...
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Blast Crisis drug therapy, Blast Crisis enzymology, Blast Crisis pathology, Cell Division drug effects, Cell Line, Tumor, Cytostatic Agents pharmacology, Gene Expression Regulation, Leukemic drug effects, Genomic Instability, Humans, Imatinib Mesylate pharmacology, Imatinib Mesylate therapeutic use, Imidazoles pharmacology, Imidazoles therapeutic use, Leukemia, Experimental drug therapy, Leukemia, Experimental enzymology, Leukemia, Experimental pathology, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase enzymology, Leukemia, Myeloid, Chronic-Phase pathology, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins physiology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells enzymology, Oncogene Proteins v-abl antagonists & inhibitors, Oncogene Proteins v-abl genetics, Oncogene Proteins, Fusion antagonists & inhibitors, Oncogene Proteins, Fusion genetics, Oxidative Stress, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-abl genetics, Pyridazines pharmacology, Pyridazines therapeutic use, Tumor Suppressor Proteins antagonists & inhibitors, Tumor Suppressor Proteins genetics, Blast Crisis genetics, Genes, Tumor Suppressor, Genes, abl, Leukemia, Experimental genetics, Leukemia, Myeloid, Chronic-Phase genetics, Oncogene Proteins v-abl physiology, Oncogene Proteins, Fusion physiology, Proto-Oncogene Proteins c-abl physiology, Tumor Suppressor Proteins physiology
- Abstract
Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examined the role of normal ABL1 in leukemias induced by oncogenic ABL1 kinases. BCR-ABL1-Abl1(-/-) cells generated highly aggressive chronic myeloid leukemia (CML)-blast phase-like disease in mice compared with less malignant CML-chronic phase-like disease from BCR-ABL1-Abl1(+/+) cells. Additionally, loss of ABL1 stimulated proliferation and expansion of BCR-ABL1 murine leukemia stem cells, arrested myeloid differentiation, inhibited genotoxic stress-induced apoptosis, and facilitated accumulation of chromosomal aberrations. Conversely, allosteric stimulation of ABL1 kinase activity enhanced the antileukemia effect of ABL1 tyrosine kinase inhibitors (imatinib and ponatinib) in human and murine leukemias expressing BCR-ABL1, TEL-ABL1, and NUP214-ABL1. Therefore, we postulate that normal ABL1 kinase behaves like a tumor suppressor and therapeutic target in leukemias expressing oncogenic forms of the kinase., (© 2016 by The American Society of Hematology.) more...
- Published
- 2016
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7. Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.
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Cramer-Morales K, Nieborowska-Skorska M, Scheibner K, Padget M, Irvine DA, Sliwinski T, Haas K, Lee J, Geng H, Roy D, Slupianek A, Rassool FV, Wasik MA, Childers W, Copland M, Müschen M, Civin CI, and Skorski T more...
- Subjects
- Animals, Aptamers, Peptide chemistry, BRCA1 Protein genetics, BRCA1 Protein metabolism, BRCA2 Protein genetics, BRCA2 Protein metabolism, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Blotting, Western, Case-Control Studies, Cell Differentiation, Cell Proliferation, DNA Damage genetics, DNA Repair genetics, Epigenomics, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl metabolism, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell prevention & control, Mice, Mice, SCID, Models, Molecular, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local prevention & control, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Oligonucleotide Array Sequence Analysis, Peptide Fragments, RNA, Messenger genetics, Rad51 Recombinase genetics, Rad51 Recombinase metabolism, Rad52 DNA Repair and Recombination Protein antagonists & inhibitors, Rad52 DNA Repair and Recombination Protein metabolism, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Apoptosis, Aptamers, Peptide pharmacology, Gene Expression Profiling, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mutation genetics, Rad52 DNA Repair and Recombination Protein genetics, Recombination, Genetic genetics
- Abstract
Homologous recombination repair (HRR) protects cells from the lethal effect of spontaneous and therapy-induced DNA double-stand breaks. HRR usually depends on BRCA1/2-RAD51, and RAD52-RAD51 serves as back-up. To target HRR in tumor cells, a phenomenon called "synthetic lethality" was applied, which relies on the addiction of cancer cells to a single DNA repair pathway, whereas normal cells operate 2 or more mechanisms. Using mutagenesis and a peptide aptamer approach, we pinpointed phenylalanine 79 in RAD52 DNA binding domain I (RAD52-phenylalanine 79 [F79]) as a valid target to induce synthetic lethality in BRCA1- and/or BRCA2-deficient leukemias and carcinomas without affecting normal cells and tissues. Targeting RAD52-F79 disrupts the RAD52-DNA interaction, resulting in the accumulation of toxic DNA double-stand breaks in malignant cells, but not in normal counterparts. In addition, abrogation of RAD52-DNA interaction enhanced the antileukemia effect of already-approved drugs. BRCA-deficient status predisposing to RAD52-dependent synthetic lethality could be predicted by genetic abnormalities such as oncogenes BCR-ABL1 and PML-RAR, mutations in BRCA1 and/or BRCA2 genes, and gene expression profiles identifying leukemias displaying low levels of BRCA1 and/or BRCA2. We believe this work may initiate a personalized therapeutic approach in numerous patients with tumors displaying encoded and functional BRCA deficiency. more...
- Published
- 2013
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8. Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells.
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Bolton-Gillespie E, Schemionek M, Klein HU, Flis S, Hoser G, Lange T, Nieborowska-Skorska M, Maier J, Kerstiens L, Koptyra M, Müller MC, Modi H, Stoklosa T, Seferynska I, Bhatia R, Holyoake TL, Koschmieder S, and Skorski T more...
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- Animals, Cells, Cultured, DNA Damage drug effects, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mice, Mice, Transgenic, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Oxidative Stress drug effects, Oxidative Stress genetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Reactive Oxygen Species metabolism, Antineoplastic Agents therapeutic use, Benzamides therapeutic use, Drug Resistance, Neoplasm genetics, Genomic Instability drug effects, Genomic Instability physiology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Neoplastic Stem Cells physiology, Piperazines therapeutic use, Pyrimidines therapeutic use
- Abstract
Genomic instability is a hallmark of chronic myeloid leukemia in chronic phase (CML-CP) resulting in BCR-ABL1 mutations encoding resistance to tyrosine kinase inhibitors (TKIs) and/or additional chromosomal aberrations leading to disease relapse and/or malignant progression. TKI-naive and TKI-treated leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) accumulate high levels of reactive oxygen species (ROS) and oxidative DNA damage. To determine the role of TKI-refractory LSCs in genomic instability, we used a murine model of CML-CP where ROS-induced oxidative DNA damage was elevated in LSCs, including quiescent LSCs, but not in LPCs. ROS-induced oxidative DNA damage in LSCs caused clinically relevant genomic instability in CML-CP-like mice, such as TKI-resistant BCR-ABL1 mutations (E255K, T315I, H396P), deletions in Ikzf1 and Trp53, and additions in Zfp423 and Idh1. Despite inhibition of BCR-ABL1 kinase, imatinib did not downregulate ROS and oxidative DNA damage in TKI-refractory LSCs to the levels detected in normal cells, and CML-CP-like mice treated with imatinib continued to accumulate clinically relevant genetic aberrations. Inhibition of class I p21-activated protein kinases by IPA3 downregulated ROS in TKI-naive and TKI-treated LSCs. Altogether, we postulate that genomic instability may originate in the most primitive TKI-refractory LSCs in TKI-naive and TKI-treated patients. more...
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- 2013
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9. Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors.
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Nieborowska-Skorska M, Kopinski PK, Ray R, Hoser G, Ngaba D, Flis S, Cramer K, Reddy MM, Koptyra M, Penserga T, Glodkowska-Mrowka E, Bolton E, Holyoake TL, Eaves CJ, Cerny-Reiterer S, Valent P, Hochhaus A, Hughes TP, van der Kuip H, Sattler M, Wiktor-Jedrzejczak W, Richardson C, Dorrance A, Stoklosa T, Williams DA, and Skorski T more...
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- Animals, Catalase metabolism, DNA Damage, DNA, Neoplasm genetics, DNA, Neoplasm metabolism, Disease Progression, Electron Transport, Fusion Proteins, bcr-abl genetics, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Membrane Potential, Mitochondrial, Methacrylates pharmacology, Mice, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplastic Stem Cells metabolism, Polycythemia Vera metabolism, Polycythemia Vera pathology, Recombinant Fusion Proteins antagonists & inhibitors, Recombinant Fusion Proteins physiology, Superoxide Dismutase metabolism, Thiazoles pharmacology, rac GTP-Binding Proteins antagonists & inhibitors, rac GTP-Binding Proteins genetics, RAC2 GTP-Binding Protein, Electron Transport Complex III metabolism, Genomic Instability, Leukemia, Myeloid, Chronic-Phase pathology, Neoplasm Proteins physiology, Neoplastic Stem Cells drug effects, Reactive Oxygen Species metabolism, rac GTP-Binding Proteins physiology
- Abstract
Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML. more...
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- 2012
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10. Targeting RAD51 phosphotyrosine-315 to prevent unfaithful recombination repair in BCR-ABL1 leukemia.
- Author
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Slupianek A, Dasgupta Y, Ren SY, Gurdek E, Donlin M, Nieborowska-Skorska M, Fleury F, and Skorski T
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- Animals, Blotting, Western, Cell Line, Tumor, Fusion Proteins, bcr-abl metabolism, Humans, Mice, Polymerase Chain Reaction, Rad51 Recombinase metabolism, Transfection, Tyrosine metabolism, DNA Repair physiology, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Rad51 Recombinase genetics
- Abstract
Chronic myeloid leukemia chronic phase (CML-CP) CD34(+) cells contain numerous DNA double-strand breaks whose unfaithful repair may contribute to chromosomal instability and disease progression to blast phase (CML-BP). These phenomena are often associated with the appearance of imatinib-resistant BCR-ABL1 kinase mutants (eg, T315I) and overexpression of BCR-ABL1. Here we show that BCR-ABL1 (nonmutated and T315I mutant) promoted RAD51 recombinase-mediated unfaithful homeologous recombination repair (HomeoRR) in a dosage-dependent manner. BCR-ABL1 SH3 domain interacts with RAD51 proline-rich regions, resulting in direct phosphorylation of RAD51 on Y315 (pY315). RAD51(pY315) facilitates dissociation from the complex with BCR-ABL1 kinase, migrates to the nucleus, and enhances formation of the nuclear foci indicative of recombination sites. HomeoRR and RAD51 nuclear foci were strongly reduced by RAD51(Y315F) phosphorylation-less mutant. In addition, peptide aptamer mimicking RAD51(pY315) fragment, but not that with Y315F phosphorylation-less substitution, diminished RAD51 foci formation and inhibited HomeoRR in leukemia cells. In conclusion, we postulate that BCR-ABL1 kinase-mediated RAD51(pY315) promotes unfaithful HomeoRR in leukemia cells, which may contribute to accumulation of secondary chromosomal aberrations responsible for CML relapse and progression. more...
- Published
- 2011
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11. Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex Mre11-RAD50-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cells.
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Rink L, Slupianek A, Stoklosa T, Nieborowska-Skorska M, Urbanska K, Seferynska I, Reiss K, and Skorski T
- Subjects
- Acid Anhydride Hydrolases, Animals, Antineoplastic Agents therapeutic use, Benzamides, Cell Survival drug effects, DNA Replication drug effects, Fusion Proteins, bcr-abl, Gene Expression Regulation, Neoplastic, Humans, Imatinib Mesylate, MRE11 Homologue Protein, Mice, Phosphorylation, Piperazines therapeutic use, Pyrimidines therapeutic use, Recombination, Genetic, Antineoplastic Agents pharmacology, Cell Cycle Proteins metabolism, DNA Repair, DNA Repair Enzymes metabolism, DNA-Binding Proteins metabolism, Leukemia drug therapy, Nuclear Proteins metabolism, Piperazines pharmacology, Protein-Tyrosine Kinases analysis, Pyrimidines pharmacology
- Abstract
Nbs1, a member of the Mre11-RAD50-Nbs1 complex, is phosphorylated by ATM, the product of the ataxia-telangiectasia mutated gene and a member of the phosphatidylinositol 3-kinase-related family of serine-threonine kinases, in response to DNA double-strand breaks (DSBs) to regulate DNA damage checkpoints. Here we show that BCR/ABL stimulated Nbs1 expression by induction of c-Myc-dependent transactivation and protection from caspase-dependent degradation. BCR/ABL-related fusion tyrosine kinases (FTKs) such as TEL/JAK2, TEL/PDGFbetaR, TEL/ABL, TEL/TRKC, BCR/FGFR1, and NPM/ALK as well as interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) also stimulated Nbs1 expression. Enhanced ATM kinase-dependent phosphorylation of Nbs1 on serine 343 (S343) in response to genotoxic treatment was detected in leukemia cells expressing BCR/ABL and other FTKs in comparison to normal counterparts stimulated with IL-3, GM-CSF, and SCF. Expression of Nbs1-S343A mutant disrupted the intra-S-phase checkpoint, decreased homologous recombinational repair (HRR) activity, down-regulated XIAP expression, and sensitized BCR/ABL-positive cells to cytotoxic drugs. Interestingly, inhibition of Nbs1 phosphorylation by S343A mutant enhanced the antileukemia effect of the combination of imatinib and genotoxic agent. more...
- Published
- 2007
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12. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance.
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Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska M, Blasiak J, and Skorski T
- Subjects
- Animals, Benzamides, Cell Line, Tumor, DNA Damage, Fusion Proteins, bcr-abl, Imatinib Mesylate, Mice, Mice, SCID, Oxidation-Reduction, Phenotype, Piperazines pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrimidines pharmacology, Drug Resistance, Neoplasm genetics, Mutagenesis, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Reactive Oxygen Species metabolism
- Abstract
Mutations in the BCR/ABL kinase domain play a major role in resistance to imatinib mesylate (IM). We report here that BCR/ABL kinase stimulates reactive oxygen species (ROS), which causes oxidative DNA damage, resulting in mutations in the kinase domain. The majority of mutations involved A/T-->G/C and G/C-->A/T transitions, a phenotype detected previously in patients, which encoded clinically relevant amino acid substitutions, causing IM resistance. This effect was reduced in cells expressing BCR/ABL(Y177F) mutant, which does not elevate ROS. Inhibition of ROS in leukemia cells by the antioxidants pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine (NAC), and vitamin E (VE) decreased the mutagenesis rate and frequency of IM resistance. Simultaneous administration of IM and an antioxidant exerted better antimutagenic effect than an antioxidant alone. Therefore, inhibition of ROS should diminish mutagenesis and enhance the effectiveness of IM. more...
- Published
- 2006
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13. BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks.
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Nowicki MO, Falinski R, Koptyra M, Slupianek A, Stoklosa T, Gloc E, Nieborowska-Skorska M, Blasiak J, and Skorski T
- Subjects
- Animals, Comet Assay, Genomic Instability, Interphase, Leukemia etiology, Mice, Mutation, Tumor Cells, Cultured, DNA Damage, DNA Repair, Fusion Proteins, bcr-abl physiology, Reactive Oxygen Species metabolism
- Abstract
The oncogenic BCR/ABL tyrosine kinase induces constitutive DNA damage in Philadelphia chromosome (Ph)-positive leukemia cells. We find that BCR/ABL-induced reactive oxygen species (ROSs) cause chronic oxidative DNA damage resulting in double-strand breaks (DSBs) in S and G(2)/M cell cycle phases. These lesions are repaired by BCR/ABL-stimulated homologous recombination repair (HRR) and nonhomologous end-joining (NHEJ) mechanisms. A high mutation rate is detected in HRR products in BCR/ABL-positive cells, but not in the normal counterparts. In addition, large deletions are found in NHEJ products exclusively in BCR/ABL cells. We propose that the following series of events may contribute to genomic instability of Ph-positive leukemias: BCR/ABL --> ROSs --> oxidative DNA damage --> DSBs in proliferating cells --> unfaithful HRR and NHEJ repair. more...
- Published
- 2004
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14. p210 BCR/ABL kinase regulates nucleotide excision repair (NER) and resistance to UV radiation.
- Author
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Canitrot Y, Falinski R, Louat T, Laurent G, Cazaux C, Hoffmann JS, Lautier D, and Skorski T
- Subjects
- Animals, Cell Survival physiology, Cell Survival radiation effects, DNA Helicases, DNA-Binding Proteins metabolism, Fusion Proteins, bcr-abl, Mice, Mutagenesis radiation effects, Proliferating Cell Nuclear Antigen metabolism, Radiation Tolerance physiology, Tumor Cells, Cultured cytology, Tumor Cells, Cultured enzymology, Tumor Cells, Cultured radiation effects, DNA Repair physiology, Protein-Tyrosine Kinases metabolism, Ultraviolet Rays
- Abstract
Both clinical and experimental evidence illustrate that p190 and p210 BCR/ABL oncogenic tyrosine kinases induce resistance to DNA damage and confer an intrinsic genetic instability. Here, we investigated whether BCR/ABL expression could modulate nucleotide excision repair (NER). We found that ectopic expression of p210 BCR/ABL in murine lymphoid BaF3 cell line inhibited NER activity in vitro, promoting hypersensitivity of these cells to ultraviolet (UV) treatment and facilitating a mutator phenotype. However, expression of p210 BCR/ABL in human and murine myeloid cell lines and primary bone marrow cells resulted in the increased NER activity and resistance to UV irradiation. The ABL tyrosine kinase inhibitor STI571 reversed these effects, showing that p210 BCR/ABL tyrosine kinase activity is responsible for deregulation of NER. Hypoactivity of NER in p210 BCR/ABL-positive lymphoid cells was accompanied by the decreased interaction between proliferating cell nuclear antigen (PCNA) and xeroderma pigmentosum group B (XPB); conversely, this interaction was enhanced in p210 BCR/ABL-positive myeloid cells. p190 BCR/ABL did not affect NER in lymphoid and myeloid cells. In summary, our study suggests that p210 BCR/ABL reduced NER activity in lymphoid cells, leading to hypersensitivity to UV and mutagenesis. In contrast, p210 BCR/ABL expression in myeloid cells facilitated NER and induced resistance to UV. more...
- Published
- 2003
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15. Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis.
- Author
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Nieborowska-Skorska M, Hoser G, Kossev P, Wasik MA, and Skorski T
- Subjects
- Animals, Apoptosis drug effects, Cell Transformation, Neoplastic metabolism, DNA-Binding Proteins drug effects, DNA-Binding Proteins metabolism, Drug Synergism, Humans, Kinetics, Mice, Protein Serine-Threonine Kinases drug effects, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins drug effects, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-pim-1, Replication Protein C, STAT5 Transcription Factor, Trans-Activators metabolism, Trans-Activators physiology, Tumor Cells, Cultured, Up-Regulation drug effects, Cell Transformation, Neoplastic drug effects, DNA-Binding Proteins physiology, Fusion Proteins, bcr-abl pharmacology, Leukemia etiology, Milk Proteins, Protein Serine-Threonine Kinases physiology, Proto-Oncogene Proteins physiology
- Abstract
BCR/ABL oncogenic tyrosine kinase activates STAT5, which plays an important role in leukemogenesis. The downstream effectors of the BCR/ABL-->STAT5 pathway remain poorly defined. We show here that expression of the antiapoptotic protein A1, a member of the Bcl-2 family, and the serine/threonine kinase pim-1 are enhanced by BCR/ABL. This up-regulation requires activation of STAT5 by the signaling from SH3+SH2 domains of BCR/ABL. Enhanced expression of A1 and pim-1 played a key role in the BCR/ABL-mediated cell protection from apoptosis. In addition, pim-1 promoted proliferation of the BCR/ABL-transformed cells. Both A1 and pim-1 were required to induce interleukin 3-independent cell growth, inhibit activation of caspase 3, and stimulate cell cycle progression. Moreover, simultaneous up-regulation of both A1 and pim-1 was essential for in vitro transformation and in vivo leukemogenesis mediated by BCR/ABL. These data indicate that induction of A1 and pim-1 expression may play a critical role in the BCR/ABL-dependent transformation. more...
- Published
- 2002
- Full Text
- View/download PDF
16. Role of p53 in hematopoietic recovery after cytotoxic treatment.
- Author
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Wlodarski P, Wasik M, Ratajczak MZ, Sevignani C, Hoser G, Kawiak J, Gewirtz AM, Calabretta B, and Skorski T
- Subjects
- Animals, Apoptosis drug effects, Gene Expression Regulation drug effects, Genes, Tumor Suppressor genetics, Hematopoiesis drug effects, Mice, Mice, Knockout, Antimetabolites toxicity, Apoptosis genetics, Fluorouracil toxicity, Hematopoiesis genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Prompt reconstitution of hematopoiesis after cytoreductive therapy is essential for patient recovery and may have a positive impact on long-term prognosis. We examined the role of the p53 tumor suppressor gene in hematopoietic recovery in vivo after treatment with the cytotoxic drug 5-fluorouracil (5-FU). We used p53 knock-out (p53-/-) and wild-type (p53+/+) mice injected with 5-FU as the experimental model. Analysis of the repopulation ability and clonogenic activity of hematopoietic stem cells (HSCs) and their lineage-committed descendants showed a greater number of HSCs responsible for reconstitution of lethally irradiated recipients in p53-/- bone marrow cells (BMCs) recovering after 5-FU treatment than in the corresponding p53+/+ BMCs. In post-5-FU recovering BMCs, the percentage of HSC-enriched Lin- Sca-1(+) c-Kit+ cells was about threefold higher in p53-/- than in p53+/+ cells. Although the percentage of the most primitive HSCs (Lin- Sca-1(+) c-Kit+ CD34(low/-)) did not depend on p53, the percentage of multipotential HSCs and committed progenitors (Lin- Sca-1(+) c-Kit+ CD34(high/+)) was almost fourfold higher in post-5-FU recovering p53-/- BMCs than in their p53+/+ counterparts. The pool of HSCs from 5-FU-treated p53-/- BMCs was exhausted more slowly than that from the p53+/+ population as shown in vivo using pre-spleen colony-forming unit (CFU-S) assay and in vitro using long-term culture-initiating cells (LTC-ICs) and methylcellulose replating assays. Clonogenic activity of various lineage-specific descendants was significantly higher in post-5-FU regenerating p53-/- BMCs than in p53+/+ BMCs, probably because of their increased sensitivity to growth factors. Despite all these changes and the dramatic difference in sensitivity of p53-/- and p53+/+ BMCs to 5-FU-induced apoptosis, lineage commitment and differentiation of hematopoietic progenitors appeared to be independent of p53 status. These studies suggest that suppression of p53 function facilitates hematopoietic reconstitution after cytoreductive therapy by: (1) delaying the exhaustion of the most primitive HSC pool, (2) stimulating the production of multipotential HSCs, (3) increasing the sensitivity of hematopoietic cells to growth factors, and (4) decreasing the sensitivity to apoptosis. more...
- Published
- 1998
17. The SH3 domain contributes to BCR/ABL-dependent leukemogenesis in vivo: role in adhesion, invasion, and homing.
- Author
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Skorski T, Nieborowska-Skorska M, Wlodarski P, Wasik M, Trotta R, Kanakaraj P, Salomoni P, Antonyak M, Martinez R, Majewski M, Wong A, Perussia B, and Calabretta B
- Subjects
- Animals, Cell Adhesion genetics, Cell Line, Leukemia, Experimental genetics, Mice, Cell Movement genetics, Cell Transformation, Neoplastic, Fusion Proteins, bcr-abl genetics, Gene Expression Regulation, Neoplastic, Leukemia, Experimental pathology, src Homology Domains genetics
- Abstract
To determine the possible role of the BCR/ABL oncoprotein SH3 domain in BCR/ABL-dependent leukemogenesis, we studied the biologic properties of a BCR/ABL SH3 deletion mutant (delta SH3 BCR/ABL) constitutively expressed in murine hematopoietic cells. delta SH3 BCR/ABL was able to activate known BCR/ABL-dependent downstream effector molecules such as RAS, PI-3kinase, MAPK, JNK, MYC, JUN, STATs, and BCL-2. Moreover, expression of delta SH3 BCR/ABL protected 32Dcl3 murine myeloid precursor cells from apoptosis, induced their growth factor-independent proliferation, and resulted in transformation of primary bone marrow cells in vitro. Unexpectedly, leukemic growth from cells expressing delta SH3 BCR/ABL was significantly retarded in SCID mice compared with that of cells expressing the wild-type protein. In vitro and in vivo studies to determine the adhesive and invasive properties of delta SH3 BCR/ABL-expressing cells showed their decreased interaction to collagen IV- and laminin-coated plates and their reduced capacity to invade the stroma and to seed the bone marrow and spleen. The decreased interaction with collagen type IV and laminin was consistent with a reduced expression of alpha 2 integrin by delta SH3 BCR/ABL-transfected 32Dcl3 cells. Moreover, as compared with wild-type BCR/ABL, which localizes primarily in the cytoskeletal/membrane fraction, delta SH3 BCR/ABL was more evenly distributed between the cytoskeleton/membrane and the cytosol compartments. Together, the data indicate that the SH3 domain of BCR/ABL is dispensable for in vitro transformation of hematopoietic cells but is essential for full leukemogenic potential in vivo. more...
- Published
- 1998
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