title: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yoda
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.forename: Michal
authors.initials: M
authors.lastname: Bar-Natan
authors.forename: Kartik
authors.initials: K
authors.lastname: Mani
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Nathan
authors.initials: N
authors.lastname: West
authors.forename: Yun
authors.initials: Y
authors.lastname: Xiao
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Martha
authors.initials: M
authors.lastname: Wadleigh
authors.forename: Alfonso
authors.initials: A
authors.lastname: Piciocchi
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
mesh_terms: D000328:Adult; D002648:Child; D016207:Cytokines / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D018121:Receptors, Cytokine / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate; D014158:Transcription, Genetic
chemical_list: C498762:CRLF2 protein, human; D016207:Cytokines; D018121:Receptors, Cytokine; D053614:Janus Kinase 2