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The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia.

ABSTRACT: Transcription factor IKZF1 (IKAROS) acts as a critical regulator of lymphoid differentiation and is frequently deleted or mutated in B-cell precursor acute lymphoblastic leukemia. IKZF1 gene defects are associated with inferior treatment outcome in both childhood and adult B-cell precursor acute lymphoblastic leukemia and occur in more than 70% of BCR-ABL1-positive and BCR-ABL1-like cases of acute lymphoblastic leukemia. Over the past few years, much has been learned about the tumor suppressive function of IKZF1 during leukemia development and the molecular pathways that relate to its impact on treatment outcome. In this review, we provide a concise overview on the role of IKZF1 during normal lymphopoiesis and the pathways that contribute to leukemia pathogenesis as a consequence of altered IKZF1 function. Furthermore, we discuss different mechanisms by which IKZF1 alterations impose therapy resistance on leukemic cells, including enhanced cell adhesion and modulation of glucocorticoid response.

SUBMITTER: Marke R

PROVIDER: S-EPMC5865415 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia.

Marke René R van Leeuwen Frank N FN Scheijen Blanca B

Haematologica 20180308 4

Transcription factor IKZF1 (IKAROS) acts as a critical regulator of lymphoid differentiation and is frequently deleted or mutated in B-cell precursor acute lymphoblastic leukemia. IKZF1 gene defects are associated with inferior treatment outcome in both childhood and adult B-cell precursor acute lymphoblastic leukemia and occur in more than 70% of BCR-ABL1-positive and BCR-ABL1-like cases of acute lymphoblastic leukemia. Over the past few years, much has been learned about t ...[more]

PMID: 29519871

Similar Datasets

IKZF1 deletion is associated with a poor outcome in pediatric B-cell precursor acute lymphoblastic leukemia in Japan.

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Absence of Genomic Ikaros/IKZF1 Deletions in Pediatric B-Precursor Acute Lymphoblastic Leukemia.

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Tumor Suppressor IKZF1 Mediates Glucocorticoid Therapy Resistance in B Cell Precursor Acute Lymphoblastic Leukemia

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2015-02-04 | E-GEOD-65554 | biostudies-arrayexpress

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Project description:BackgroundDespite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined.MethodsWe studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL.ResultsMore than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion.ConclusionsGenetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL.

| S-EPMC2674612 | biostudies-literature

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Tumor Suppressor IKZF1 Mediates Glucocorticoid Therapy Resistance in B Cell Precursor Acute Lymphoblastic Leukemia

2015-02-04 | GSE65554 | GEO

Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia.

Project description:Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high-risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here, we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest, and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.

| S-EPMC4573904 | biostudies-literature

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