Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors

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dc.contributor.authorWaibel, M.
dc.contributor.authorSolomon, V.
dc.contributor.authorKnight, D.
dc.contributor.authorRalli, R.
dc.contributor.authorKim, S.
dc.contributor.authorBanks, K.
dc.contributor.authorVidacs, E.
dc.contributor.authorVirely, C.
dc.contributor.authorSia, K.
dc.contributor.authorBracken, L.
dc.contributor.authorCollins-Underwood, R.
dc.contributor.authorDrenberg, C.
dc.contributor.authorRamsey, L.
dc.contributor.authorMeyer, S.
dc.contributor.authorTakiguchi, M.
dc.contributor.authorDickins, R.
dc.contributor.authorLevine, R.
dc.contributor.authorGhysdael, J.
dc.contributor.authorDawson, M.
dc.contributor.authorLock, R.
dc.contributor.authoret al.
dc.date.issued2013
dc.description.abstractTo design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.
dc.description.statementofresponsibilityMichaela Waibel, Vanessa S. Solomon, Deborah A. Knight, Rachael A. Ralli, Sang-Kyu Kim, Kellie-Marie Banks, Eva Vidacs, Clemence Virely, Keith C.S. Sia, Lauryn S. Bracken, Racquel Collins-Underwood, Christina Drenberg, Laura B. Ramsey, Sara C. Meyer, Megumi Takiguchi, Ross A. Dickins, Ross Levine, Jacques Ghysdael, Mark A. Dawson, Richard B. Lock, Charles G. Mullighan and Ricky W. Johnstone
dc.identifier.citationCell reports, 2013; 5(4):1047-1059
dc.identifier.doi10.1016/j.celrep.2013.10.038
dc.identifier.issn2211-1247
dc.identifier.issn2211-1247
dc.identifier.orcidMullighan, C. [0000-0002-1871-1850]
dc.identifier.urihttp://hdl.handle.net/2440/103601
dc.language.isoen
dc.publisherCell Press
dc.relation.grantNHMRC
dc.rights©2013 The Authors, This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1016/j.celrep.2013.10.038
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Inbred NOD
dc.subjectHumans
dc.subjectMice
dc.subjectMice, SCID
dc.subjectSulfonamides
dc.subjectBiphenyl Compounds
dc.subjectNitriles
dc.subjectNitrophenols
dc.subjectPiperazines
dc.subjectPyrazoles
dc.subjectPyrimidines
dc.subjectMembrane Proteins
dc.subjectProto-Oncogene Proteins
dc.subjectTransplantation, Heterologous
dc.subjectGene Expression Profiling
dc.subjectNeoplasm Transplantation
dc.subjectSignal Transduction
dc.subjectApoptosis
dc.subjectCell Survival
dc.subjectDrug Resistance, Neoplasm
dc.subjectApoptosis Regulatory Proteins
dc.subjectbcl-X Protein
dc.subjectJanus Kinase 2
dc.subjectPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma
dc.subjectBcl-2-Like Protein 11
dc.titleCombined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors
dc.typeJournal article
pubs.publication-statusPublished

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