Person: Chapuy, Bjoern
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Publication Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition
(The Rockefeller University Press, 2012) Weigert, Oliver; Bird, Liat; Kopp, Nadja; van Bodegom, Diederik; Marubayashi, Sachie; Christie, Amanda L.; Paranal, Ronald M.; Gaul, Christoph; Vangrevelinghe, Eric; Romanet, Vincent; Murakami, Masato; Tiedt, Ralph; Ebel, Nicolas; Evrot, Emeline; De Pover, Alain; Régnier, Catherine H.; Erdmann, Dirk; Hofmann, Francesco; Levine, Ross L.; Baffert, Fabienne; Radimerski, Thomas; Lane, Andrew; Chapuy, Bjoern; Toms, Angela Vivian; McKeown, Michael Robert; Bradner, James E; Yoda, Akinori; Eck, Michael; Sallan, Stephen; Kung, Andrew; Weinstock, DavidEnzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor–like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100–1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.
Publication 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, DavidDown 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.