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

Akinori Yoda, Yuka Yoda, Sabina Chiaretti, Michal Bar-Natan, Kartik Mani, Scott J. Rodig, Nathan West, Yun Xiao, Jennifer R. Brown, Constantine Mitsiades, Martin Sattler, Jeffrey L. Kutok, Daniel J. DeAngelo, Martha Wadleigh, Alfonso Piciocchi, Paola Dal Cin, James E. Bradner, James D. Griffin, Kenneth C. Anderson, Richard M. StoneJerome Ritz, Robin Foà, Jon C. Aster, David A. Frank, David M. Weinstock

Research output: Contribution to journalArticlepeer-review

238 Scopus citations

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 BALL 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.

Original languageEnglish
Pages (from-to)252-257
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number1
DOIs
StatePublished - 2010

Keywords

  • JAK2
  • TSLP
  • TSLPR

Fingerprint

Dive into the research topics of 'Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia'. Together they form a unique fingerprint.

Cite this