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      Clinical characteristics and outcomes of B-ALL with ZNF384 rearrangements: a retrospective analysis by the Ponte di Legno Childhood ALL Working Group

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          Most cited references14

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          Acute Lymphoblastic Leukemia in Children.

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            PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia

            Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL, incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription factor gene PAX5 . One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations), and a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.
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              A causal mechanism for childhood acute lymphoblastic leukaemia

              In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.
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                Author and article information

                Contributors
                atmanabe@med.hokudai.ac.jp
                Journal
                Leukemia
                Leukemia
                Leukemia
                Nature Publishing Group UK (London )
                0887-6924
                1476-5551
                10 March 2021
                10 March 2021
                2021
                : 35
                : 11
                : 3272-3277
                Affiliations
                [1 ]GRID grid.39158.36, ISNI 0000 0001 2173 7691, Department of Pediatrics, , Hokkaido University Graduate School of Medicine, ; Sapporo, Japan
                [2 ]GRID grid.1006.7, ISNI 0000 0001 0462 7212, Leukaemia Research Cytogenetics Group, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, , Newcastle University, ; Newcastle upon Tyne, UK
                [3 ]GRID grid.63906.3a, ISNI 0000 0004 0377 2305, Department of Pediatric Hematology and Oncology Research, , National Research Institute for Child Health and Development, ; Tokyo, Japan
                [4 ]GRID grid.10388.32, ISNI 0000 0001 2240 3300, Hannover Medical School, , Institute of Human Genetics, ; Hannover, Germany
                [5 ]GRID grid.9764.c, ISNI 0000 0001 2153 9986, Department of Pediatrics, , Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, ; Kiel, Germany
                [6 ]GRID grid.487647.e, Princess Máxima Center for Pediatric Oncology, ; Utrecht, Netherlands
                [7 ]GRID grid.499559.d, Oncode Institute, ; Utrecht, Netherlands
                [8 ]GRID grid.413235.2, ISNI 0000 0004 1937 0589, Department of Genetics, , Robert Debré Hospital and University of Paris, ; Paris, France
                [9 ]GRID grid.7563.7, ISNI 0000 0001 2174 1754, Centro Ricerca Tettamanti, , Pediatric Clinic University of Milano-Bicocca, ; Monza, Italy
                [10 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, Khoo Teck Puat - National University Children’s Medical Institute, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, Singapore
                [11 ]GRID grid.410840.9, ISNI 0000 0004 0378 7902, Department of Advanced Diagnosis, Clinical Research Center, , National Hospital Organization Nagoya Medical Center, ; Nagoya, Japan
                [12 ]GRID grid.272458.e, ISNI 0000 0001 0667 4960, Department of Pediatrics, Graduate School of Medical Science, , Kyoto Prefectural University of Medicine, ; Kyoto, Japan
                [13 ]GRID grid.267301.1, ISNI 0000 0004 0386 9246, St Jude Children’s Research Hospital and Department of Pediatrics, College of Medicine, , The University of Tennessee Health Science Center, ; Memphis, TN USA
                [14 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, , University of California, San Francisco, ; San Francisco, CA USA
                [15 ]GRID grid.12650.30, ISNI 0000 0001 1034 3451, Department of Clinical Sciences, Pediatrics, , Umeå University, ; Umeå, Sweden
                [16 ]GRID grid.8267.b, ISNI 0000 0001 2165 3025, Department of Pediatric, Oncology, Hematology and Diabetology, , Medical University of Łódź, ; Poland, CA Poland
                [17 ]GRID grid.145695.a, ISNI 0000 0004 1798 0922, Division of Hematology-Oncology, , Chang Gung Memorial Hospital at Linkou and Chang Gung University, ; Taoyuan, Taiwan
                [18 ]GRID grid.4491.8, ISNI 0000 0004 1937 116X, CLIP, Department of Paediatric Haematology/Oncology, , Charles University Prague, 2nd Faculty of Medicine, ; Prague, Czech Republic
                [19 ]GRID grid.416346.2, Children’s Cancer Research Institute, ; Vienna, Austria
                Author information
                http://orcid.org/0000-0001-7961-0968
                http://orcid.org/0000-0003-2840-1511
                http://orcid.org/0000-0002-6454-976X
                http://orcid.org/0000-0003-0605-7342
                http://orcid.org/0000-0002-1871-1850
                http://orcid.org/0000-0002-1639-7124
                http://orcid.org/0000-0003-0303-5658
                http://orcid.org/0000-0001-7334-454X
                http://orcid.org/0000-0002-9781-6107
                http://orcid.org/0000-0002-6698-2348
                Article
                1199
                10.1038/s41375-021-01199-0
                8550960
                33692463
                083d7b80-126b-4e9d-8366-3ec3e308ed3c
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 July 2020
                : 21 January 2021
                : 18 February 2021
                Categories
                Letter
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                © The Author(s), under exclusive licence to Springer Nature Limited 2021

                Oncology & Radiotherapy
                acute lymphocytic leukaemia,cancer genetics
                Oncology & Radiotherapy
                acute lymphocytic leukaemia, cancer genetics

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