title: Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+pre-B ALL.
abstract: Inactivation of the tumor suppressor gene encoding the transcriptional regulator Ikaros (IKZF1) is a hallmark of BCR-ABL1+precursor B cell acute lymphoblastic leukemia (pre-B ALL). However, the mechanisms by which Ikaros functions as a tumor suppressor in pre-B ALL remain poorly understood. Here, we analyzed a mouse model of BCR-ABL1+pre-B ALL together with a new model of inducible expression of wild-type Ikaros inIKZF1mutant human BCR-ABL1+pre-B ALL. We performed integrated genome-wide chromatin and expression analyses and identified Ikaros target genes in mouse and human BCR-ABL1+pre-B ALL, revealing novel conserved gene pathways associated with Ikaros tumor suppressor function. Notably, genetic depletion of different Ikaros targets, includingCTNND1and the early hematopoietic cell surface marker CD34, resulted in reduced leukemic growth. Our results suggest that Ikaros mediates tumor suppressor function by enforcing proper developmental stage-specific expression of multiple genes through chromatin compaction at its target genes.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143 Hilde.Schjerven@ucsf.edu Seth.Frietze@med.uvm.edu.
authors.forename: Hilde
authors.identifier: 0000-0001-9287-3375
authors.initials: H
authors.lastname: Schjerven
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143.|Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Etapong F
authors.identifier: 0000-0003-2960-9808
authors.initials: EF
authors.lastname: Ayongaba
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
authors.forename: Ali
authors.initials: A
authors.lastname: Aghajanirefah
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
authors.forename: Jami
authors.initials: J
authors.lastname: McLaughlin
authors.affiliation: Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.
authors.forename: Donghui
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, VT 05405.
authors.forename: Joseph R
authors.identifier: 0000-0002-8969-9676
authors.initials: JR
authors.lastname: Boyd
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143.|Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Linn M
authors.initials: LM
authors.lastname: Eggesbø
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143.|Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Ida
authors.identifier: 0000-0001-8343-2842
authors.initials: I
authors.lastname: Lindeman
authors.affiliation: Department of Pediatrics, University of Vermont, Burlington, VT 05405.|Department of Biochemistry, University of Vermont, Burlington, VT 05405.
authors.forename: Jessica L
authors.identifier: 0000-0003-1771-2242
authors.initials: JL
authors.lastname: Heath
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
authors.forename: Eugene
authors.identifier: 0000-0001-8432-5168
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.|Molecular Biology Institute, University of California, Los Angeles, CA 90095.
authors.forename: Owen N
authors.identifier: 0000-0003-4461-4533
authors.initials: ON
authors.lastname: Witte
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.|Molecular Biology Institute, University of California, Los Angeles, CA 90095.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smale
authors.affiliation: Department of Medical Laboratory and Radiation Science, University of Vermont, Burlington, VT 05405 Hilde.Schjerven@ucsf.edu Seth.Frietze@med.uvm.edu.
authors.forename: Seth
authors.initials: S
authors.lastname: Frietze
authors.affiliation: Department of Systems Biology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Pasadena, CA 91016.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000032:analysis*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000502:physiology*; D051917:Leukosialin / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D018952:Antigens, CD34; C581634:BCR-ABL1 fusion protein, human; C497239:IKZF1 protein, human; D051917:Leukosialin; D025521:Tumor Suppressor Proteins; D051740:Ikaros Transcription Factor; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl