Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia.
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.
Yoda
Akinori
A
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Yoda
Yuka
Y
Chiaretti
Sabina
S
Bar-Natan
Michal
M
Mani
Kartik
K
Rodig
Scott J
SJ
West
Nathan
N
Xiao
Yun
Y
Brown
Jennifer R
JR
Mitsiades
Constantine
C
Sattler
Martin
M
Kutok
Jeffrey L
JL
DeAngelo
Daniel J
DJ
Wadleigh
Martha
M
Piciocchi
Alfonso
A
Dal Cin
Paola
P
Bradner
James E
JE
Griffin
James D
JD
Anderson
Kenneth C
KC
Stone
Richard M
RM
Ritz
Jerome
J
Foà
Robin
R
Aster
Jon C
JC
Frank
David A
DA
Weinstock
David M
DM
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
C498762:CRLF2 protein, human; D016207:Cytokines; D018121:Receptors, Cytokine; D053614:Janus Kinase 2