Page 21 - Haematologica-April 2018

The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia
René Marke,1 Frank N. van Leeuwen1 and Blanca Scheijen1,2
1Laboratory of Pediatric Oncology, Radboud University Medical Center, and 2Department of Pathology, Radboud University Medical Center; Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, the Netherlands
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 lym- phoblastic leukemia. Over the past few years, much has been learned about the tumor suppressive function of IKZF1 during leukemia develop- ment 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 alter- ations impose therapy resistance on leukemic cells, including enhanced cell adhesion and modulation of glucocorticoid response.
Introduction
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in children and involves uncontrolled expansion of B-lymphoid progen- itors in the bone marrow. The disease is frequently initiated by a chromosomal translocation but becomes manifest only when leukemic progenitors in the bone marrow have accumulated a number of additional gene deletions and mutations that drive disease progression. With current treatment protocols long-term survival approaches 90%;1 however, relapses still pose a significant clinical challenge due to resistance to chemotherapy of the recurrent disease.1 Both in pediatric and adult BCP-ALL, specific genetic subtypes with distinct prognostic outcomes can be iden- tified2 Some of these subtypes, such as hyperdiploid ALL and ETV6-RUNX1- rearranged ALL are associated with a favorable outcome, while other genetic hall- marks, such as MLL gene rearrangements, hypodiploidy, intrachromosomal translocation of chromosome 21 (iAMP21), or the presence of the t(9;22) BCR-ABL1 translocation predict poor outcome. Moreover, the presence of a gene expression profile similar to that of BCR-ABL1-positive ALL, which frequently involves genetic alterations that deregulate cytokine receptor and/or tyrosine kinase signaling, is similarly associated with poor outcome.2 In addition to these gross chromosomal rearrangements, deletions or mutations affecting the B-cell transcription factor IKZF1, are a strong and independent predictor of poor outcome in BCP-ALL.3,4 Together with its role as a critical regulator of B-cell development and a leukemia tumor suppressor, there is mounting evidence that IKZF1 loss also affects signaling pathways that modulate therapy response.
Here, we provide an overview of the complex role of transcription factor IKZF1 during normal lymphopoiesis and consequences of IKZF1 loss for the pathogenesis of BCP-ALL. Finally, we discuss some of the molecular mechanisms by which IKZF1 gene alterations may contribute to therapy resistance.
Transcription regulation by IKAROS zinc-finger protein 1
The IKAROS family of transcription factors consists of five different IKAROS zinc-finger proteins (IKZF1-IKZF5) that are able to bind DNA directly at the core
Ferrata Storti Foundation
Haematologica 2018 Volume 103(4):565-574
Correspondence:
blanca.scheijen@radboudumc.nl
Received: November29,2017. Accepted: February 12, 2018. Pre-published: March 8, 2018.
doi:10.3324/haematol.2017.185603
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/4/565
©2018 Ferrata Storti Foundation
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