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.
Harvey
Richard C
RC
University of New Mexico Cancer Center and Departments of Pathology and Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
Mullighan
Charles G
CG
Chen
I-Ming
IM
Wharton
Walker
W
Mikhail
Fady M
FM
Carroll
Andrew J
AJ
Kang
Huining
H
Liu
Wei
W
Dobbin
Kevin K
KK
Smith
Malcolm A
MA
Carroll
William L
WL
Devidas
Meenakshi
M
Bowman
W Paul
WP
Camitta
Bruce M
BM
Reaman
Gregory H
GH
Hunger
Stephen P
SP
Downing
James R
JR
Willman
Cheryl L
CL
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