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Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre-B ALL.

The Journal of experimental medicine | 2017

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.

Pubmed ID: 28190001 RIS Download

Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK043726
  • Agency: NCI NIH HHS, United States
    Id: R01 CA213138
  • Agency: NCI NIH HHS, United States
    Id: R01 CA157644
  • Agency: NCI NIH HHS, United States
    Id: R01 CA172558
  • Agency: NCI NIH HHS, United States
    Id: R01 CA169458
  • Agency: NCI NIH HHS, United States
    Id: R21 CA209229
  • Agency: NCI NIH HHS, United States
    Id: R35 CA197628
  • Agency: NCI NIH HHS, United States
    Id: R01 CA139032
  • Agency: NCI NIH HHS, United States
    Id: R01 CA137060
  • Agency: Howard Hughes Medical Institute, United States

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