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

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          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.

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          THE GENOMIC LANDSCAPE OF PEDIATRIC AND YOUNG ADULT T-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA

          Yu Liu, John Easton, Ying Shao … (2017)
          Genetic alterations activating NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors are hallmarks of T-ALL, but detailed genome-wide sequencing of large T-ALL cohorts has not been performed. Using integrated genomic analysis of 264 T-ALL cases, we identify 106 putative driver genes, half of which were not previously described in childhood T-ALL (e.g. CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We described new mechanisms of coding and non-coding alteration, and identify 10 recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOX1 deregulated ALL, PTPN2 mutations in TLX1 T-ALL, and PIK3R1/PTEN mutations in TAL1 ALL, suggesting that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.
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            Genetic Basis of Acute Lymphoblastic Leukemia

            Ilaria Iacobucci, Charles Mullighan (2017)
            Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and despite cure rates exceeding 90% in children, it remains an important cause of morbidity and mortality in children and adults. The past decade has been marked by extraordinary advances into the genetic basis of leukemogenesis and treatment responsiveness in ALL. Both B-cell and T-cell ALL comprise multiple subtypes harboring distinct constellations of somatic structural DNA rearrangements and sequence mutations that commonly perturb lymphoid development, cytokine receptors, kinase and Ras signaling, tumor suppression, and chromatin modification. Recent studies have helped to understand the genetic basis of clonal evolution and relapse and the role of inherited genetic variants in leukemogenesis. Many of these findings are of clinical importance, and ongoing studies implementing clinical sequencing in the management of leukemia are expected to improve diagnosis, monitoring of residual disease, and early detection of relapse and to guide precise therapies. Here, we provide a concise review of genomic studies in ALL and discuss the role of genomic testing in clinical management.
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              The Ikaros gene is required for the development of all lymphoid lineages.

              Katia Georgopoulos, Michael Bigby, Jin-Hong Wang … (1994)
              The Ikaros gene encodes a family of early hematopoietic- and lymphocyte-restricted transcription factors. Mice homozygous for a germline mutation in the Ikaros DNA-binding domain lack not only T and B lymphocytes and natural killer cells but also their earliest defined progenitors. In contrast, the erythroid and myeloid lineages were intact in these mutant mice. We propose that Ikaros promotes differentiation of pluripotential hematopoietic stem cell(s) into the lymphocyte pathways. In the absence of a functional Ikaros gene, these stem cells are exclusively diverted into the erythroid and myeloid lineages.
              Article 0 comments Cited 156 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Haematologica
                Journal ID (iso-abbrev): Haematologica
                Journal ID (hwp): haematol
                Journal ID (publisher-id): Haematologica
                Title: Haematologica
                Publisher: Ferrata Storti Foundation
                ISSN (Print): 0390-6078
                ISSN (Electronic): 1592-8721
                Publication date (Print): April 2018
                Publication date (Electronic preprint): 8 March 2018
                Volume: 103
                Issue: 4
                Pages: 565-574
                Affiliations
                [1 ]Laboratory of Pediatric Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
                [2 ]Department of Pathology, Radboud University Medical Center; Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, the Netherlands
                Author notes
                Article
                Publisher ID: 1030565
                DOI: 10.3324/haematol.2017.185603
                PMC ID: 5865415
                PubMed ID: 29519871
                SO-VID: 5d3afbfb-992d-4aea-b82c-3f33bce6056d
                Copyright © Copyright© 2018 Ferrata Storti Foundation
                License:

                Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.

                History
                Date received : 29 November 2017
                Date accepted : 12 February 2018
                Categories
                Subject: Review Article

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