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  1. Article ; Online: Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia.

    Kamens, Jennifer L / Nance, Stephanie / Koss, Cary / Xu, Beisi / Cotton, Anitria / Lam, Jeannie W / Garfinkle, Elizabeth A R / Nallagatla, Pratima / Smith, Amelia M R / Mitchell, Sharnise / Ma, Jing / Currier, Duane / Wright, William C / Kavdia, Kanisha / Pagala, Vishwajeeth R / Kim, Wonil / Wallace, LaShanale M / Cho, Ji-Hoon / Fan, Yiping /
    Seth, Aman / Twarog, Nathaniel / Choi, John K / Obeng, Esther A / Hatley, Mark E / Metzger, Monika L / Inaba, Hiroto / Jeha, Sima / Rubnitz, Jeffrey E / Peng, Junmin / Chen, Taosheng / Shelat, Anang A / Guy, R Kiplin / Gruber, Tanja A

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 809

    Abstract: Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. ... ...

    Abstract Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.
    MeSH term(s) Infant ; Adult ; Humans ; Child ; Proteasome Endopeptidase Complex/genetics ; Lysine/genetics ; Myeloid-Lymphoid Leukemia Protein/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Transcriptome
    Chemical Substances Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Lysine (K3Z4F929H6) ; Myeloid-Lymphoid Leukemia Protein (149025-06-9)
    Language English
    Publishing date 2023-02-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-36370-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Author Correction: Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia.

    Kamens, Jennifer L / Nance, Stephanie / Koss, Cary / Xu, Beisi / Cotton, Anitria / Lam, Jeannie W / Garfinkle, Elizabeth A R / Nallagatla, Pratima / Smith, Amelia M R / Mitchell, Sharnise / Ma, Jing / Currier, Duane / Wright, William C / Kavdia, Kanisha / Pagala, Vishwajeeth R / Kim, Wonil / Wallace, LaShanale M / Cho, Ji-Hoon / Fan, Yiping /
    Seth, Aman / Twarog, Nathaniel / Choi, John K / Obeng, Esther A / Hatley, Mark E / Metzger, Monika L / Inaba, Hiroto / Jeha, Sima / Rubnitz, Jeffrey E / Peng, Junmin / Chen, Taosheng / Shelat, Anang A / Guy, R Kiplin / Gruber, Tanja A

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 1297

    Language English
    Publishing date 2023-03-09
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-37141-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Analysis of lysine recognition and specificity of the Bacillus subtilis L box riboswitch.

    Wilson-Mitchell, Sharnise N / Grundy, Frank J / Henkin, Tina M

    Nucleic acids research

    2012  Volume 40, Issue 12, Page(s) 5706–5717

    Abstract: The ever-changing environment of a bacterial cell requires sophisticated mechanisms to adjust gene expression in response to changes in nutrient availability. L box riboswitch RNAs regulate gene expression in response to cellular lysine (lys) ... ...

    Abstract The ever-changing environment of a bacterial cell requires sophisticated mechanisms to adjust gene expression in response to changes in nutrient availability. L box riboswitch RNAs regulate gene expression in response to cellular lysine (lys) concentrations in the absence of additional regulatory factors. In Bacillus subtilis, binding of lysine (lys) to the L box RNA causes premature transcription termination in the leader region upstream of the lysC coding sequence. To date, little is known about the specific RNA-lys interactions required for transcription termination. In this study, we characterize features of the B. subtilis lysC leader RNA responsible for lys specificity, and structural elements of the lys molecule required for recognition. The wild-type lysC leader RNA can recognize and discriminate between lys and lys analogs. We identified leader RNA variants with mutations in the lys-binding pocket that exhibit changes in the specificity of ligand recognition. These data demonstrate that lysC leader RNA specificity is the result of recognition of ligand features through a series of distinct interactions between lys and nucleotides that comprise the lys-binding pocket, and provide insight into the molecular mechanisms employed by L box riboswitch RNAs to bind and recognize lys.
    MeSH term(s) 5' Untranslated Regions ; Aspartate Kinase/biosynthesis ; Aspartate Kinase/genetics ; Bacillus subtilis/enzymology ; Bacillus subtilis/genetics ; Base Sequence ; Binding Sites ; Gene Expression Regulation, Bacterial ; Ligands ; Lysine/analogs & derivatives ; Lysine/chemistry ; Lysine/pharmacology ; Molecular Sequence Data ; Mutation ; Potassium/chemistry ; RNA, Bacterial/chemistry ; Riboswitch ; Transcription, Genetic
    Chemical Substances 5' Untranslated Regions ; Ligands ; RNA, Bacterial ; Riboswitch ; lysC aspartokinase (EC 2.7.2.-) ; Aspartate Kinase (EC 2.7.2.4) ; Lysine (K3Z4F929H6) ; Potassium (RWP5GA015D)
    Language English
    Publishing date 2012-03-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gks212
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

    Kimura, Shunsuke / Polonen, Petri / Montefiori, Lindsey / Park, Chun Shik / Iacobucci, Ilaria / Yeoh, Allen Ej / Attarbaschi, Andishe / Moore, Andrew S / Brown, Anthony / Manabe, Atsushi / Buldini, Barbara / Freeman, Burgess B / Chen, Chelsey / Cheng, Cheng / Kean Hui, Chiew / Li, Chi-Kong / Pui, Ching-Hon / Qu, Chunxu / Tomizawa, Daisuke /
    Teachey, David T / Varotto, Elena / Paietta, Elisabeth M / Arnold, Elizabeth D / Locatelli, Franco / Escherich, Gabriele / Elisa Muhle, Hannah / Marquart, Hanne Vibeke / de Groot-Kruseman, Hester A / Rowe, Jacob M / Stary, Jan / Trka, Jan / Choi, John Kim / Meijerink, Jules P P / Yang, Jun J / Takita, Junko / Pawinska-Wasikowska, Katarzyna / Roberts, Kathryn G / Han, Katie / Caldwell, Kenneth J / Schmiegelow, Kjeld / Crews, Kristine R / Eguchi, Mariko / Schrappe, Martin / Zimmerman, Martin / Takagi, Masatoshi / Maybury, Mellissa / Svaton, Michael / Reiterova, Michaela / Kicinski, Michal / Prater, Mollie S / Kato, Motohiro / Reyes, Noemi / Spinelli, Orietta / Thomas, Paul / Mazilier, Pauline / Gao, Qingsong / Masetti, Riccardo / Kotecha, Rishi S / Pieters, Rob / Elitzur, Sarah / Luger, Selina M / Mitchell, Sharnise / Pruett-Miller, Shondra M / Shen, Shuhong / Jeha, Sima / Köhrer, Stefan / Kornblau, Steven M / Skoczeń, Szymon / Miyamura, Takako / Vincent, Tiffaney L / Imamura, Toshihiko / Conter, Valentino / Tang, Yanjing / Liu, Yen-Chun / Chang, Yunchao / Gu, Zhaohui / Cheng, Zhongshan / Yinmei, Zhou / Inaba, Hiroto / Mullighan, Charles G

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: Purpose: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.: Methods: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 ... ...

    Abstract Purpose: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.
    Methods: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts.
    Results: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10],
    Conclusion: γδ T-ALL in children under the age of three is extremely high-risk and enriched for
    Support: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173.
    Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.
    Language English
    Publishing date 2023-11-08
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.06.23298028
    Database MEDical Literature Analysis and Retrieval System OnLINE

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