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Schinzel, Anna

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Schinzel

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Anna

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Schinzel, Anna
Author's Publications: search.filters.isAuthorOfPublication.31aca90d-cbbd-4b1b-8fab-af0d215777f4

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    Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 lysine 27 trimethylation
    (2014) Lane, Andrew; Chapuy, Bjoern; Lin, Charles Y.; Tivey, Trevor; Li, Hubo; Townsend, Elizabeth C.; van Bodegom, Diederik; Day, Tovah; Wu, Shuo-Chieh; Liu, Huiyun; Yoda, Akinori; Alexe, Gabriela; Schinzel, Anna; Sullivan, Timothy J.; Malinge, Sébastien; Taylor, Jordan E.; Stegmaier, Kimberly; Jaffe, Jacob D.; Bustin, Michael; te Kronnie, Geertruy; Izraeli, Shai; Harris, Marian; Stevenson, Kristen E.; Neuberg, Donna; Silverman, Lewis; Sallan, Stephen; Bradner, James E; Hahn, William; Crispino, John D.; Pellman, David; Weinstock, David
    Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL)1 and polysomy 21 is the most frequent somatic aneuploidy amongst all B-ALLs2. Yet, the mechanistic links between chr.21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 confers murine progenitor B cell self-renewal in vitro, maturation defects in vivo, and B-ALL with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in progenitor B cells and B-ALLs, and “bivalent” genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q223–5, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.
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    CK1\(\varepsilon\) is Required for Breast Cancers Dependent on \(\beta\)-Catenin Activity
    (Public Library of Science, 2010) Firestein, Ron; Gupta, Piyush; Repich, Kara; Silver, Serena J.; Boehm, Jesse S.; Kim, So Young; Dunn, Ian; Wardwell, Leslie; Schinzel, Anna; Wittner, Ben; Root, David E.; Ramaswamy, Sridhar; Lander, Eric; Hahn, William
    Background: Aberrant \(\beta\)-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate \(\beta\)-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active \(\beta\)-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized \(\beta\)-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1\(\varepsilon\)) as required specifically for the proliferation of breast cancer cells with activated \(\beta\)-catenin and confirm its role as a positive regulator of \(\beta\)-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated \(\beta\)-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/\(\beta\)-catenin signaling. We also find that expression of CK1\(\varepsilon\) is able to promote oncogenic transformation of human cells in a \(\beta\)-catenin-dependent manner. Conclusions/Significance: These studies identify CK1\(\varepsilon\) as a critical contributor to activated \(\beta\)-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active \(\beta\)-catenin. More generally, these observations delineate an approach that can be used to identify druggable synthetic lethal interactions with signaling pathways that are frequently activated in cancer but are difficult to target with the currently available small molecule inhibitors.