Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia

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dc.contributor.authorTasian, S.
dc.contributor.authorDoral, M.
dc.contributor.authorBorowitz, M.
dc.contributor.authorWood, B.
dc.contributor.authorChen, I.-M.
dc.contributor.authorHarvey, R.
dc.contributor.authorGastier-Foster, J.
dc.contributor.authorWillman, C.
dc.contributor.authorHunger, S.
dc.contributor.authorMullighan, C.
dc.contributor.authorLoh, M.
dc.date.issued2012
dc.description.abstractAdults and children with high-risk CRLF2-rearranged acute lymphoblastic leukemia (ALL) respond poorly to current cytotoxic chemotherapy and suffer unacceptably high rates of relapse, supporting the need to use alternative therapies. CRLF2 encodes the thymic stromal lymphopoietin (TSLP) receptor, which activates cell signaling in normal lymphocytes on binding its ligand, TSLP. We hypothesized that aberrant cell signaling occurs in CRLF2-rearranged ALL and can be targeted by signal transduction inhibitors of this pathway. In a large number of primary CRLF2-rearranged ALL samples, we observed increased basal levels of pJAK2, pSTAT5, and pS6. We thus characterized the biochemical sequelae of CRLF2 and JAK alterations in CRLF2-rearranged ALL primary patient samples via analysis of TSLP-mediated signal transduction. TSLP stimulation of these leukemias further induced robust JAK/STAT and PI3K/mTOR pathway signaling. JAK inhibition abrogated phosphorylation of JAK/STAT and, surprisingly, of PI3K/mTOR pathway members, suggesting an interconnection between these signaling networks and providing a rationale for testing JAK inhibitors in clinical trials. The PI3K/mTOR pathway inhibitors rapamycin, PI103, and PP242 also inhibited activated signal transduction and translational machinery proteins of the PI3K/mTOR pathway, suggesting that signal transduction inhibitors targeting this pathway also may have therapeutic relevance for patients with CRLF2-rearranged ALL and merit further preclinical testing.
dc.description.statementofresponsibilitySarah K. Tasian, Michelle Y. Doral, Michael J. Borowitz, Brent L. Wood, I-Ming Chen, Richard C. Harvey, Julie M. Gastier-Foster, Cheryl L. Willman, Stephen P. Hunger, Charles G. Mullighan and Mignon L. Loh
dc.identifier.citationBlood, 2012; 120(4):833-842
dc.identifier.doi10.1182/blood-2011-12-389932
dc.identifier.issn0006-4971
dc.identifier.issn1528-0020
dc.identifier.orcidMullighan, C. [0000-0002-1871-1850]
dc.identifier.urihttp://hdl.handle.net/2440/106541
dc.language.isoen
dc.publisherAmerican Society of Hematology
dc.rights© 2012 by The American Society of Hematology
dc.source.urihttps://doi.org/10.1182/blood-2011-12-389932
dc.subjectTumor Cells, Cultured
dc.subjectHumans
dc.subjectReceptors, Cytokine
dc.subjectRNA, Messenger
dc.subjectBlotting, Western
dc.subjectFlow Cytometry
dc.subjectIn Situ Hybridization, Fluorescence
dc.subjectSignal Transduction
dc.subjectCell Proliferation
dc.subjectGene Rearrangement
dc.subjectPoint Mutation
dc.subjectAdult
dc.subjectChild
dc.subjectSTAT5 Transcription Factor
dc.subjectPrecursor B-Cell Lymphoblastic Leukemia-Lymphoma
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectTOR Serine-Threonine Kinases
dc.subjectReal-Time Polymerase Chain Reaction
dc.titleAberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia
dc.typeJournal article
pubs.publication-statusPublished

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