Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.
Gene expression profiling of 207 uniformly treated children with high-risk B-progenitor acute lymphoblastic leukemia revealed 29 of 207 cases (14%) with markedly elevated expression of CRLF2 (cytokine receptor-like factor 2). Each of the 29 cases harbored a genomic rearrangement of CRLF2: 18 of 29 (62%) had a translocation of the immunoglobulin heavy chain gene IGH@ on 14q32 to CRLF2 in the pseudoautosomal region 1 of Xp22.3/Yp11.3, whereas 10 (34%) cases had a 320-kb interstitial deletion centromeric of CRLF2, resulting in a P2RY8-CRLF2 fusion. One case had both IGH@-CRLF2 and P2RY8-CRLF2, and another had a novel CRLF2 rearrangement. Only 2 of 29 cases were Down syndrome. CRLF2 rearrangements were significantly associated with activating mutations of JAK1 or JAK2, deletion or mutation of IKZF1, and Hispanic/Latino ethnicity (Fisher exact test, P < .001 for each). Within this cohort, patients with CRLF2 rearrangements had extremely poor treatment outcomes compared with those without CRLF2 rearrangements (35.3% vs 71.3% relapse-free survival at 4 years; P < .001). Together, these observations suggest that activation of CRLF2 expression, mutation of JAK kinases, and alterations of IKZF1 cooperate to promote B-cell leukemogenesis and identify these pathways as important therapeutic targets in this disease.
University of New Mexico Cancer Center and Departments of Pathology and Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
Richard C
RC
Harvey
Charles G
CG
Mullighan
I-Ming
IM
Chen
Walker
W
Wharton
Fady M
FM
Mikhail
Andrew J
AJ
Carroll
Huining
H
Kang
Wei
W
Liu
Kevin K
KK
Dobbin
Malcolm A
MA
Smith
William L
WL
Carroll
Meenakshi
M
Devidas
W Paul
WP
Bowman
Bruce M
BM
Camitta
Gregory H
GH
Reaman
Stephen P
SP
Hunger
James R
JR
Downing
Cheryl L
CL
Willman
D000293:Adolescent; D002648:Child; D015331:Cohort Studies; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D053613:Janus Kinase 1 / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics; D053612:Janus Kinases / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology / Q000235:genetics*; D018121:Receptors, Cytokine / Q000235:genetics*
C498762:CRLF2 protein, human; C497239:IKZF1 protein, human; D018121:Receptors, Cytokine; D051740:Ikaros Transcription Factor; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053612:Janus Kinases