Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group.
We report gene expression and other analyses to elucidate the molecular characteristics of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL samples analyzed were characterized by high expression of the type I cytokine receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations or by interstitial deletions creating chimeric transcripts P2RY8-CRLF2. In 3 of these 33 patients, a novel activating somatic mutation, F232C in CRLF2, was identified. Consistent with our previous research, mutations in R683 of JAK2 were identified in 10 specimens (19% of the patients) and, interestingly, all 10 had high CRLF2 expression. Cytokine receptor-like factor 2 (CRLF2) and mutated Janus kinase 2 (Jak2) cooperated in conferring cytokine-independent growth to BaF3 pro-B cells. Intriguingly, the gene expression signature of DS-ALL is enriched with DNA damage and BCL6 responsive genes, suggesting the possibility of B-cell lymphocytic genomic instability. Thus, DS confers increased risk for genetically highly diverse ALLs with frequent overexpression of CRLF2, associated with activating mutations in the receptor itself or in JAK2. Our data also suggest that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathways.
Hertzberg
Libi
L
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Vendramini
Elena
E
Ganmore
Ithamar
I
Cazzaniga
Gianni
G
Schmitz
Maike
M
Chalker
Jane
J
Shiloh
Ruth
R
Iacobucci
Ilaria
I
Shochat
Chen
C
Zeligson
Sharon
S
Cario
Gunnar
G
Stanulla
Martin
M
Strehl
Sabine
S
Russell
Lisa J
LJ
Harrison
Christine J
CJ
Bornhauser
Beat
B
Yoda
Akinori
A
Rechavi
Gideon
G
Bercovich
Dani
D
Borkhardt
Arndt
A
Kempski
Helena
H
te Kronnie
Geertruy
G
Bourquin
Jean-Pierre
JP
Domany
Eytan
E
Izraeli
Shai
S
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004314:Down Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018740:Genetic Heterogeneity; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D018121:Receptors, Cytokine / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C084103:BCL6 protein, human; C498762:CRLF2 protein, human; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D018121:Receptors, Cytokine; C507924:JAK2 protein, human; D053614:Janus Kinase 2