title: Clinical significance of high c-MYC and low MYCBP2 expression and their association with Ikaros dysfunction in adult acute lymphoblastic leukemia.
abstract: Increased expression of c-MYC is observed in both Acute Myeloid Leukemia (AML) and T-cell Acute Lymphoblastic Leukemia (T-ALL). MYC binding protein 2 (MYCBP2) is a probable E3 ubiquitin ligase and its function in leukemia is unknown. IKZF1 deletion is associated with the development and poor outcome of ALL. Here, we observed significant high c-MYC expression and low MYCBP2 expression in adult ALL patients. Patients with high c-MYC expression and/or low MYCBP2 expression had higher WBC counts and a higher percentage of CD34+ or CD33+ cells, as well as splenomegaly, liver infiltration, higher BM blasts, and lower CR rate. Ikaros bound to the regulatory regions of c-MYC and MYCBP2, suppressed c-MYC and increased MYCBP2 expression in ALL cells. Expression of c-MYC mRNA was significantly higher in patients with IKZF1 deletion; conversely MYCBP2 mRNA expression was significantly lower in those patients. A CK2 inhibitor, which acts as an Ikaros activator, also suppressed c-MYC and increased MYCBP2 expression in an Ikaros (IKZF1) dependent manner in the ALL cells. In summary, our data indicated the correlation of high c-MYC expression, low MYCBP2 expression and high c-MYC plus low MYCBP2 expression with high-risk factors and proliferation markers in adult ALL patients. Our data also revealed an oncogenic role for an Ikaros/MYCBP2/c-MYC axis in adult ALL, providing a mechanism of target therapies that activate Ikaros in adult ALL.
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.|Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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: 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: Jianyong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hartman
authors.affiliation: Departments of Biochemistry and Molecular Biology and Pharmacology, Institute for Personalized Medicine, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Yuka Imamura
authors.initials: YI
authors.lastname: Kawasawa
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Dovat
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; 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 / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C497239:IKZF1 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051740:Ikaros Transcription Factor; C114022:MYCBP2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: ALL; Ikaros; MYCBP2; adult leukemia; c-MYC