1. Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL
- Author
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Schjerven, Hilde, Ayongaba, Etapong F, Aghajanirefah, Ali, McLaughlin, Jami, Cheng, Donghui, Geng, Huimin, Boyd, Joseph R, Eggesbø, Linn M, Lindeman, Ida, Heath, Jessica L, Park, Eugene, Witte, Owen N, Smale, Stephen T, Frietze, Seth, and Müschen, Markus
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Childhood Leukemia ,Human Genome ,Pediatric ,Rare Diseases ,Pediatric Cancer ,Biotechnology ,Hematology ,Genetics ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Antigens ,CD34 ,Cell Cycle ,Cell Line ,Tumor ,Fusion Proteins ,bcr-abl ,Gene Expression Regulation ,Leukemic ,Humans ,Ikaros Transcription Factor ,Leukosialin ,Mice ,Mice ,Inbred C57BL ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Proto-Oncogene Proteins c-kit ,Tumor Suppressor Proteins ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - 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 in IKZF1 mutant 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, including CTNND1 and 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.
- Published
- 2017