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 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.

• Authors: Hilde Schjerven, Etapong F Ayongaba, Ali Aghajanirefah, Jami McLaughlin, Donghui Cheng, Huimin Geng, Joseph R Boyd, Linn M Eggesbø, Ida Lindeman, Jessica L Heath, Eugene Park, Owen N Witte, Stephen T Smale, Seth Frietze, Markus Müschen
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 214 Issue 3 Pg. 793-814 (03 06 2017) ISSN: 1540-9538 [Electronic] United States
• PMID: 28190001 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2017 Schjerven et al.

Chemical References

• Antigens, CD34
• BCR-ABL1 fusion protein, human
• IKZF1 protein, human
• Leukosialin
• Tumor Suppressor Proteins
• Ikaros Transcription Factor
• Proto-Oncogene Proteins c-kit
• Fusion Proteins, bcr-abl

Topics

• Animals
• Antigens, CD34 (analysis)
• Cell Cycle
• Cell Line, Tumor
• Fusion Proteins, bcr-abl (analysis)
• Gene Expression Regulation, Leukemic
• Humans
• Ikaros Transcription Factor (genetics, physiology)
• Leukosialin (analysis)
• Mice
• Mice, Inbred C57BL
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (genetics)
• Proto-Oncogene Proteins c-kit (genetics)
• Tumor Suppressor Proteins (physiology)