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  1. Article ; Online: Reverse Phase Protein Array Profiling Identifies Recurrent Protein Expression Patterns of DNA Damage-Related Proteins across Acute and Chronic Leukemia

    Fieke W. Hoff / Ti’ara L. Griffen / Brandon D. Brown / Terzah M. Horton / Jan Burger / William Wierda / Stefan E. Hubner / Yihua Qiu / Steven M. Kornblau

    International Journal of Molecular Sciences, Vol 24, Iss 5460, p

    Samples from Adults and the Children’s Oncology Group

    2023  Volume 5460

    Abstract: DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array ... ...

    Abstract DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) ( n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) ( n = 361) and chronic lymphocytic leukemia (CLL) ( n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in T-ALL and AML (six and eleven proteins, respectively), but not CLL ( n = 0). Most (96%) of the CLL cases clustered in one cluster; the other 4% were characterized by higher frequencies of deletion 13q and 17p, and fared poorly ( p < 0.001). T-ALL predominated in C1 and AML in C5, but both occurred in all four acute-dominated clusters. Protein clusters showed similar implications for survival and remission duration in pediatric and adult T-ALL and AML populations, with C5 doing best in all. In summary, DNADR and DDR protein expression was abnormal in leukemia and formed recurrent clusters that were shared across the leukemias with shared prognostic implications across diseases, and individual proteins showed age- and disease-related differences.
    Keywords leukemia ; RPPA ; DNA damage ; proteomics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 612
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: DNA Damage Response−Related Proteins Are Prognostic for Outcome in Both Adult and Pediatric Acute Myelogenous Leukemia Patients

    Stefan E. Hubner / Eduardo S. de Camargo Magalhães / Fieke W. Hoff / Brandon D. Brown / Yihua Qiu / Terzah M. Horton / Steven M. Kornblau

    International Journal of Molecular Sciences, Vol 24, Iss 5898, p

    Samples from Adults and from Children Enrolled in a Children’s Oncology Group Study

    2023  Volume 5898

    Abstract: The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients ... ...

    Abstract The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients and were probed with 412 and 296 strictly validated antibodies, respectively, including those detecting the expression of proteins directly involved in DDR. Unbiased hierarchical clustering identified strong recurrent DDR protein expression patterns in both adult and pediatric AML. Globally, DDR expression was associated with gene mutational statuses and was prognostic for outcomes including overall survival (OS), relapse rate, and remission duration (RD). In adult patients, seven DDR proteins were individually prognostic for either RD or OS. When DDR proteins were analyzed together with DDR−related proteins operating in diverse cellular signaling pathways, these expanded groupings were also highly prognostic for OS. Analysis of patients treated with either conventional chemotherapy or venetoclax combined with a hypomethylating agent revealed protein clusters that differentially predicted favorable from unfavorable prognoses within each therapy cohort. Collectively, this investigation provides insight into variable DDR pathway activation in AML and may help direct future individualized DDR−targeted therapies in AML patients.
    Keywords AML ; proteomics ; RPPA ; DNA damage ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: The Anti-Tumor Activity of the NEDD8 Inhibitor Pevonedistat in Neuroblastoma

    Jennifer H. Foster / Eveline Barbieri / Linna Zhang / Kathleen A. Scorsone / Myrthala Moreno-Smith / Peter Zage / Terzah M. Horton

    International Journal of Molecular Sciences, Vol 22, Iss 6565, p

    2021  Volume 6565

    Abstract: Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin–RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the ... ...

    Abstract Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin–RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136–400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53 MUT ) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53 WT ) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg ( p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.
    Keywords pevonedistat ; cell cycle ; xenograft ; rereplication ; cullin–ring ligase ; ubiquitination ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616 ; 572
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Comparison of the blood, bone marrow, and cerebrospinal fluid metabolomes in children with b-cell acute lymphoblastic leukemia

    Jeremy M. Schraw / J. P. Woodhouse / Melanie B. Bernhardt / Olga A. Taylor / Terzah M. Horton / Michael E. Scheurer / M. Fatih Okcu / Karen R. Rabin / Philip J. Lupo / Austin L. Brown

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 8

    Abstract: Abstract Metabolomics may shed light on treatment response in childhood acute lymphoblastic leukemia (ALL), however, most assessments have analyzed bone marrow or cerebrospinal fluid (CSF), which are not collected during all phases of therapy. Blood is ... ...

    Abstract Abstract Metabolomics may shed light on treatment response in childhood acute lymphoblastic leukemia (ALL), however, most assessments have analyzed bone marrow or cerebrospinal fluid (CSF), which are not collected during all phases of therapy. Blood is collected frequently and with fewer risks, but it is unclear whether findings from marrow or CSF biomarker studies may translate. We profiled end-induction plasma, marrow, and CSF from N = 10 children with B-ALL using liquid chromatography-mass spectrometry. We estimated correlations between plasma and marrow/CSF metabolite abundances detected in ≥ 3 patients using Spearman rank correlation coefficients (r s ). Most marrow metabolites were detected in plasma (N = 661; 81%), and we observed moderate-to-strong correlations (median r s 0.62, interquartile range [IQR] 0.29–0.83). We detected 328 CSF metabolites in plasma (90%); plasma-CSF correlations were weaker (median r s 0.37, IQR 0.07–0.70). We observed plasma-marrow correlations for metabolites in pathways associated with end-induction residual disease (pyruvate, asparagine) and plasma-CSF correlations for a biomarker of fatigue (gamma-glutamylglutamine). There is considerable overlap between the plasma, marrow, and CSF metabolomes, and we observed strong correlations for biomarkers of clinically relevant phenotypes. Plasma may be suitable for biomarker studies in B-ALL.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia

    Natalia Baran / Alessia Lodi / Yogesh Dhungana / Shelley Herbrich / Meghan Collins / Shannon Sweeney / Renu Pandey / Anna Skwarska / Shraddha Patel / Mathieu Tremblay / Vinitha Mary Kuruvilla / Antonio Cavazos / Mecit Kaplan / Marc O. Warmoes / Diogo Troggian Veiga / Ken Furudate / Shanti Rojas-Sutterin / Andre Haman / Yves Gareau /
    Anne Marinier / Helen Ma / Karine Harutyunyan / May Daher / Luciana Melo Garcia / Gheath Al-Atrash / Sujan Piya / Vivian Ruvolo / Wentao Yang / Sriram Saravanan Shanmugavelandy / Ningping Feng / Jason Gay / Di Du / Jun J. Yang / Fieke W. Hoff / Marcin Kaminski / Katarzyna Tomczak / R. Eric Davis / Daniel Herranz / Adolfo Ferrando / Elias J. Jabbour / M. Emilia Di Francesco / David T. Teachey / Terzah M. Horton / Steven Kornblau / Katayoun Rezvani / Guy Sauvageau / Mihai Gagea / Michael Andreeff / Koichi Takahashi / Joseph R. Marszalek

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 20

    Abstract: Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis ... ...

    Abstract Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis in preclinical murine and human xenograft models.
    Keywords Science ; Q
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy

    Denise Niewerth / Gertjan J. L. Kaspers / Gerrit Jansen / Johan van Meerloo / Sonja Zweegman / Gaye Jenkins / James A. Whitlock / Stephen P. Hunger / Xiaomin Lu / Todd A. Alonzo / Peter M. van de Ven / Terzah M. Horton / Jacqueline Cloos

    Journal of Hematology & Oncology, Vol 9, Iss 1, Pp 1-

    2016  Volume 9

    Abstract: Abstract Background Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL). ... ...

    Abstract Abstract Background Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL). Methods We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children’s Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1) and AML (COG-AAML07P1). Expression of proteasome subunits was examined in 72 patient samples (ALL n = 60, AML n = 12) obtained before start of therapy. Statistical significance between groups was determined by Mann-Whitney U test. Results Ratios of immunoproteasome to constitutive proteasome subunit expression were significantly higher in pre-B ALL cells than in AML cells for both β5i/β5 and β1i/β1 subunits (p = 0.004 and p < 0.001). These ratios correlated with therapy response in AML patients; β1i/β1 ratios were significantly higher (p = 0.028) between patients who did (n = 4) and did not reach complete remission (CR) (n = 8), although for β5i/β5 ratios, this did not reach significance. For ALL patients, the subunit ratios were also higher for patients who showed a good early response to therapy but this relation was not statistically significant. Overall, for this study, the patients were treated with combination therapy, so response was not only attributed to proteasome inhibition. Moreover, the leukaemic blast cells were not purified for these samples. Conclusions These first ex vivo results encourage further studies into relative proteasome subunit expression to improve proteasome inhibition-containing therapy and as a potential indicator of bortezomib response in acute leukaemia.
    Keywords Pediatric acute leukaemia ; Bortezomib ; Proteasome inhibitor ; Immunoproteasome ; Diseases of the blood and blood-forming organs ; RC633-647.5 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
    Subject code 610
    Language English
    Publishing date 2016-09-01T00:00:00Z
    Publisher BioMed Central
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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