Analysis of Ikaros tumor suppressor function in BCR-ABL1+ pre-B ALL reveals conserved target genes and biological pathways

• DOI: 10.4049/jimmunol.196.supp.122.6
• Publication Date: 2023-01-01T10:25:23Z
• Authors: Hilde Schjerven; Etapong Fonabei A...; Jami McLaughlin; Donghui Cheng; Linn Margrethe Eg...; Ida Lindeman; Eugene Park; Owen N Witte; Stephen T Smale; Seth Frietze; Markus Muschen
• Keywords: Pediatric; 0303 health sciences; Pediatric Cancer; Childhood Leukemia; 1.1 Normal biological development and functioning; Human Genome; Immunology; Hematology; Stem Cell Research; 03 medical and health sciences; Orphan Drug; Rare Diseases; Underpinning research; Genetics; 2.1 Biological and endogenous factors; Aetiology; Biotechnology; Cancer

Abstract Inactivation of the transcriptional factor Ikaros (IKZF1) correlates with poor prognosis in progenitor B-cell acute lymphoblastic leukemia (pre-B ALL), and is a hallmark of the BCR-ABL1+ subgroup of pre-B ALL. Ikaros is a critical regulator of hematopoietic development and required for B-cell development, however the mechanisms by which Ikaros functions as a tumor suppressor in pre-B ALL remain poorly understood. We analyzed recently developed mouse models of BCR-ABL1+ pre-B ALL containing targeted deletions of Ikaros DNA-binding zinc finger domains together with a new model of inducible expression of WT Ikaros in IKZF1-mutant human BCR-ABL1+ pre-B ALL. We found that both the mouse and human Ikaros-mutated leukemic cells displayed a less mature cell surface phenotype and failed to downregulate the developmentally restricted cell surface receptors c-kit and CD34, respectively. In addition, Ctnnd1, a gene that is also expressed in earlier hematopoietic progenitor cells and normally downregulated as cells differentiate down the B-cell lineage, was found to be a conserved Ikaros target gene, with increased expression in Ikaros-mutated leukemic cells. RNA sequencing defined the Ikaros target genes in both mouse and human Ikaros-mutated pre-B ALL cells and revealed additional conserved target genes and biological functions. Loss of Ikaros tumor suppression was associated with deregulated adhesion pathways and stem-cell signatures. Furthermore, our results presented herein suggest that Ikaros mediates tumor suppressor function, at least in part, by enforcing proper developmental-stage specific expression of multiple genes involved in a network of cadherin-dependent, Rho-regulated Wnt/b-catenin pathways.