当前位置： SCI文献检索 > PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA期刊下所有文献 > Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia.

Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia.

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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Yoda A,Yoda Y,Chiaretti S,Bar-Natan M,Mani K,Rodig SJ,West N,Xiao Y,Brown JR,Mitsiades C,Sattler M,Kutok JL,DeAngelo DJ,Wadleigh M,Piciocchi A,Dal Cin P,Bradner JE,Griffin JD,Anderson KC,Stone RM,Ritz J,Foà R,

doi

10.1073/pnas.0911726107

subject

Has Abstract

pub_date

2010-01-05 00:00:00

pages

252-7

issue

eissn

0027-8424

issn

1091-6490

pii

0911726107

journal_volume

107

pub_type

杂志文章

在线工具

Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia.