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

Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):252-7. doi: 10.1073/pnas.0911726107. Epub 2009 Dec 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Cytokines / metabolism
  • DNA Mutational Analysis
  • Female
  • Humans
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Male
  • Mutation
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / diagnosis
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Prognosis
  • Receptors, Cytokine / genetics*
  • Receptors, Cytokine / metabolism
  • Signal Transduction / physiology*
  • Survival Rate
  • Transcription, Genetic


  • CRLF2 protein, human
  • Cytokines
  • Receptors, Cytokine
  • Janus Kinase 2