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Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia.
Proc Natl Acad Sci U S A 2010; 107(1):252-7PN

Abstract

The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor, in part from a lack of therapeutic targets. We identified the type I cytokine receptor subunit CRLF2 in a functional screen for B-ALL-derived mRNA transcripts that can substitute for IL3 signaling. We demonstrate that CRLF2 is overexpressed in approximately 15% of adult and high-risk pediatric B-ALL that lack MLL, TCF3, TEL, and BCR/ABL rearrangements, but not in B-ALL with these rearrangements or other lymphoid malignancies. CRLF2 overexpression can result from translocation with the IGH locus or intrachromosomal deletion and is associated with poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional signature that significantly overlaps with a BCR/ABL signature, and is enriched for genes involved in cytokine receptor and JAK-STAT signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-of-function mutation that promotes constitutive dimerization and cytokine independent growth. A mutually exclusive subset harbors activating mutations in JAK2. In fact, all 22 B-ALLs with mutant JAK2 that we analyzed overexpress CRLF2, distinguishing CRLF2 as the key scaffold for mutant JAK2 signaling in B-ALL. Expression of WT CRLF2 with mutant JAK2 also promotes cytokine independent growth that, unlike CRLF2 Phe232Cys or ligand-induced signaling by WT CRLF2, is accompanied by JAK2 phosphorylation. Finally, cells dependent on CRLF2 signaling are sensitive to small molecule inhibitors of either JAKs or protein kinase C family kinases. Together, these findings implicate CRLF2 as an important factor in B-ALL with diagnostic, prognostic, and therapeutic implications.

Authors+Show Affiliations

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20018760

Citation

Yoda, Akinori, et al. "Functional Screening Identifies CRLF2 in Precursor B-cell Acute Lymphoblastic Leukemia." Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 1, 2010, pp. 252-7.
Yoda A, Yoda Y, Chiaretti S, et al. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2010;107(1):252-7.
Yoda, A., Yoda, Y., Chiaretti, S., Bar-Natan, M., Mani, K., Rodig, S. J., ... Weinstock, D. M. (2010). Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proceedings of the National Academy of Sciences of the United States of America, 107(1), pp. 252-7. doi:10.1073/pnas.0911726107.
Yoda A, et al. Functional Screening Identifies CRLF2 in Precursor B-cell Acute Lymphoblastic Leukemia. Proc Natl Acad Sci USA. 2010 Jan 5;107(1):252-7. PubMed PMID: 20018760.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. AU - Yoda,Akinori, AU - Yoda,Yuka, AU - Chiaretti,Sabina, AU - Bar-Natan,Michal, AU - Mani,Kartik, AU - Rodig,Scott J, AU - West,Nathan, AU - Xiao,Yun, AU - Brown,Jennifer R, AU - Mitsiades,Constantine, AU - Sattler,Martin, AU - Kutok,Jeffrey L, AU - DeAngelo,Daniel J, AU - Wadleigh,Martha, AU - Piciocchi,Alfonso, AU - Dal Cin,Paola, AU - Bradner,James E, AU - Griffin,James D, AU - Anderson,Kenneth C, AU - Stone,Richard M, AU - Ritz,Jerome, AU - Foà,Robin, AU - Aster,Jon C, AU - Frank,David A, AU - Weinstock,David M, Y1 - 2009/12/15/ PY - 2009/12/19/entrez PY - 2009/12/19/pubmed PY - 2010/3/10/medline SP - 252 EP - 7 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 107 IS - 1 N2 - The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor, in part from a lack of therapeutic targets. We identified the type I cytokine receptor subunit CRLF2 in a functional screen for B-ALL-derived mRNA transcripts that can substitute for IL3 signaling. We demonstrate that CRLF2 is overexpressed in approximately 15% of adult and high-risk pediatric B-ALL that lack MLL, TCF3, TEL, and BCR/ABL rearrangements, but not in B-ALL with these rearrangements or other lymphoid malignancies. CRLF2 overexpression can result from translocation with the IGH locus or intrachromosomal deletion and is associated with poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional signature that significantly overlaps with a BCR/ABL signature, and is enriched for genes involved in cytokine receptor and JAK-STAT signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-of-function mutation that promotes constitutive dimerization and cytokine independent growth. A mutually exclusive subset harbors activating mutations in JAK2. In fact, all 22 B-ALLs with mutant JAK2 that we analyzed overexpress CRLF2, distinguishing CRLF2 as the key scaffold for mutant JAK2 signaling in B-ALL. Expression of WT CRLF2 with mutant JAK2 also promotes cytokine independent growth that, unlike CRLF2 Phe232Cys or ligand-induced signaling by WT CRLF2, is accompanied by JAK2 phosphorylation. Finally, cells dependent on CRLF2 signaling are sensitive to small molecule inhibitors of either JAKs or protein kinase C family kinases. Together, these findings implicate CRLF2 as an important factor in B-ALL with diagnostic, prognostic, and therapeutic implications. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/20018760/Functional_screening_identifies_CRLF2_in_precursor_B_cell_acute_lymphoblastic_leukemia_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=20018760 DB - PRIME DP - Unbound Medicine ER -