title: High CRLF2 expression associates with IKZF1 dysfunction in adult acute lymphoblastic leukemia without CRLF2 rearrangement.
abstract: Overexpression of cytokine receptor-like factor 2 (CRLF2) due to chromosomal rearrangement has been observed in acute lymphoblastic leukemia (ALL) and reported to contribute to oncogenesis and unfavorable outcome in ALL. We studied B-ALL and T-ALL patients without CRLF2 rearrangement and observed that CRLF2 is significantly increased in a subset of these patients. Our study shows that high CRLF2expression correlates with high-risk ALL markers, as well as poor survival. We found that the IKZF1-encoded protein, Ikaros, directly binds to the CRLF2 promoter and regulates CRLF2 expression in leukemia cells. CK2 inhibitor, which can increase Ikaros activity, significantly increases Ikaros binding in ALL cells and suppresses CRLF2 expression in an Ikaros-dependent manner. CRLF2 expression is significantly higher in patients with IKZF1 deletion as compared to patients without IKZF1 deletion. Treatment with CK2 inhibitor also results in an increase in IKZF1 binding to the CRLF2 promoter and suppression of CRLF2 expression in primary ALL cells. We further observed that CK2 inhibitor induces increased H3K9me3 histone modifications in the CRLF2 promoter in ALL cell lines and primary cells. Taken together, our results demonstrate that high expression of CRLF2 correlates with high-risk ALL and short survival in patients without CRLF2 rearrangement. Our results are the first to demonstrate that the IKZF1-encoded Ikaros protein directly suppresses CRLF2 expression through enrichment of H3K9me3 in its promoter region. Our data also suggest that high CRLF2 expression works with the IKZF1 deletion to drive oncogenesis of ALL and has significance in an integrated prognostic model for adult high-risk ALL.
authors.affiliation: Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
authors.forename: Baoan
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Han
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA, 17033, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Sydney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, 19107 USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Yu
authors.affiliation: University of Wisconsin at Stout, Menomonie, WI, 54751, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Olson
authors.affiliation: Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA, 17033, USA.
authors.forename: Sadie
authors.initials: S
authors.lastname: Steffens
authors.affiliation: Loma Linda University, Department of Pathology and Human Anatomy, Loma Linda, CA, 92350, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Payne
authors.affiliation: Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA, 17033, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA, 17033, USA.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Dovat
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C498762:CRLF2 protein, human; D002843:Chromatin; C497239:IKZF1 protein, human; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine; D051740:Ikaros Transcription Factor
keywords: CRLF2; IKZF1; acute lymphoblastic leukemia; adult