title: Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group study.
abstract: As controversy exists regarding the prognostic significance of genomic rearrangements of CRLF2 in pediatric B-precursor acute lymphoblastic leukemia (ALL) classified as standard/intermediate-risk (SR) or high-risk (HR), we assessed the prognostic significance of CRLF2 mRNA expression, CRLF2 genomic lesions (IGH@-CRLF2, P2RY8-CRLF2, CRLF2 F232C), deletion/mutation in genes frequently associated with high CRLF2 expression (IKZF1, JAK, IL7R), and minimal residual disease (MRD) in 1061 pediatric ALL patients (499 HR and 562 SR) on COG Trials P9905/P9906. Whereas very high CRLF2 expression was found in 17.5% of cases, only 51.4% of high CRLF2 expressors had CRLF2 genomic lesions. The mechanism underlying elevated CRLF2 expression in cases lacking known genomic lesions remains to be determined. All CRLF2 genomic lesions and virtually all JAK mutations were found in high CRLF2 expressors, whereas IKZF1 deletions/mutations were distributed across the full cohort. In multivariate analyses, NCI risk group, MRD, high CRLF2 expression, and IKZF1 lesions were associated with relapse-free survival. Within HR ALL, only MRD and CRLF2 expression predicted a poorer relapse-free survival; no difference was seen between cases with or without CRLF2 genomic lesions. Thus, high CRLF2 expression is associated with a very poor outcome in high-risk, but not standard-risk, ALL. This study is registered at www.clinicaltrials.gov as NCT00005596 and NCT00005603.
authors.affiliation: Cancer Center and Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131-001, USA.
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Julie
authors.initials: J
authors.lastname: Gastier-Foster
authors.forename: Walker
authors.initials: W
authors.lastname: Wharton
authors.forename: Huining
authors.initials: H
authors.lastname: Kang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Camitta
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: D Jeanette
authors.initials: DJ
authors.lastname: Pullen
authors.forename: Debbie
authors.initials: D
authors.lastname: Payne-Turner
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tasian
authors.forename: Shalini
authors.initials: S
authors.lastname: Reshmi
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Cottrell
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
authors.forename: W Paul
authors.initials: WP
authors.lastname: Bowman
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Winick
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007223:Infant; D053612:Janus Kinases / Q000235:genetics*; D008297:Male; D008495:Medical Oncology / Q000458:organization & administration; D015233:Models, Statistical; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D018121:Receptors, Cytokine / Q000235:genetics*; D012955:Societies, Medical; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C498762:CRLF2 protein, human; C497239:IKZF1 protein, human; D018121:Receptors, Cytokine; D051740:Ikaros Transcription Factor; D053612:Janus Kinases