Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre-B ALL.
J Exp Med, 2017/03/06;214(3):793-814.
Schjerven H[1], Ayongaba EF[2, 3], Aghajanirefah A[2], McLaughlin J[4], Cheng D[5], Geng H[2], Boyd JR[6], Eggesbø LM[2, 3], Lindeman I[2, 3], Heath JL[7, 8], Park E[2], Witte ON[4, 5, 9], Smale ST[4, 5, 9], Frietze S[10], Müschen M[11]
Affiliations
PMID: 28190001DOI: 10.1084/jem.20160049
Impact factor: 17.579
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.
MeSH terms
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
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