PMID- 30578714 OWN - NLM STAT- MEDLINE DCOM- 20190520 LR - 20190816 IS - 1098-2264 (Electronic) IS - 1045-2257 (Linking) VI - 58 IP - 6 DP - 2019 Jun TI - Non-leukemic pediatric mixed phenotype acute leukemia/lymphoma: Genomic characterization and clinical outcome in a prospective trial for pediatric lymphoblastic lymphoma. PG - 365-372 LID - 10.1002/gcc.22726 [doi] AB - Rare cases of hematological precursor neoplasms fulfill the diagnostic criteria of mixed phenotype acute leukemia (MPAL), characterized by expression patterns of at least two hematopoietic lineages, for which a highly aggressive behavior was reported. We present a series of 11 pediatric non-leukemic MPAL identified among 146 precursor lymphoblastic lymphomas included in the prospective trial Euro-LBL 02. Paraffin-embedded biopsies of 10 cases were suitable for molecular analyses using OncoScan assay (n = 7), fluorescence in situ hybridization (FISH; n = 7) or both (n = 5). Except for one case with biallelic KMT2A (MLL) breaks, all cases analyzed by FISH lacked the most common translocations defining molecular subsets of lymphoblastic leukemia/lymphomas. Two non-leukemic B-myeloid MPALs showed the typical genomic profile of hyperdiploid precursor B-cell lymphoblastic leukemia with gains of chromosomes 4, 6, 10, 14, 18, and 21. One B-T MPAL showed typical aberrations of T-cell lymphoblastic lymphoma, such as copy number neutral loss of heterozygosity (CNN-LOH) at 9p targeting a 9p21.3 deletion of CDKN2A and 11q12.2-qter affecting the ATM gene. ATM was also mutated in a T-myeloid MPAL case with additional loss at 7q21.2-q36.3 and mutation of NRAS, two alterations common in myeloid disorders. No recurrent regions of CNN-LOH were observed. The outcome under treatment was good with all patients being alive in first complete remission after treatment according to a protocol for precursor lymphoblastic lymphoma (follow-up 3-10 years, median: 4.9 years). In summary, the present series of non-leukemic MPALs widely lacked recurrently reported translocations in lymphoid/myeloid neoplasias and showed heterogeneous spectrum of chromosomal imbalances. CI - (c) 2018 Wiley Periodicals, Inc. FAU - Martin-Guerrero, Idoia AU - Martin-Guerrero I AD - Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany. AD - Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country, Leioa, Spain. FAU - Salaverria, Itziar AU - Salaverria I AD - Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany. AD - Department of Pathology, Hematopathology Unit, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), CIBERONC, University of Barcelona, Barcelona, Spain. FAU - Burkhardt, Birgit AU - Burkhardt B AD - NHL-BFM Study Center and Department of Pediatric Hematology and Oncology, University Children's Hospital, Munster, Germany. FAU - Chassagne-Clement, Catherine AU - Chassagne-Clement C AD - Department of Biopathology, Centre Leon Berard, Lyon, France. FAU - Szczepanowski, Monika AU - Szczepanowski M AD - Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany. FAU - Bens, Susanne AU - Bens S AD - Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany. AD - Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany. FAU - Klapper, Wolfram AU - Klapper W AD - Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany. FAU - Zimmermann, Martin AU - Zimmermann M AD - Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany. FAU - Kabickova, Edita AU - Kabickova E AD - Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University Prague and University Hospital Motol, Motol, Czech Republic. FAU - Bertrand, Yves AU - Bertrand Y AD - Department of Pediatric Hematology, IHOP and Claude Bernard University, Lyon, France. FAU - Reiter, Alfred AU - Reiter A AD - Department of Pediatric Hematology and Oncology, NHL-BFM-Study Center Justus Liebig University, Germany. FAU - Siebert, Reiner AU - Siebert R AD - Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany. AD - Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany. FAU - Oschlies, Ilske AU - Oschlies I AUID- ORCID: 0000-0002-4003-6855 AD - Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany. LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190121 PL - United States TA - Genes Chromosomes Cancer JT - Genes, chromosomes & cancer JID - 9007329 RN - 0 (Antineoplastic Agents) RN - 0 (CDKN2A protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p16) RN - 0 (KMT2A protein, human) RN - 0 (Membrane Proteins) RN - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) RN - EC 2.7.11.1 (ATM protein, human) RN - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 3.6.1.- (GTP Phosphohydrolases) RN - EC 3.6.1.- (NRAS protein, human) SB - IM MH - Adolescent MH - Antineoplastic Agents/adverse effects/therapeutic use MH - Ataxia Telangiectasia Mutated Proteins/genetics MH - Child MH - Child, Preschool MH - Cyclin-Dependent Kinase Inhibitor p16/genetics MH - Female MH - GTP Phosphohydrolases/genetics MH - Genomic Instability/drug effects MH - Histone-Lysine N-Methyltransferase/genetics MH - Humans MH - Male MH - Membrane Proteins/genetics MH - Myeloid-Lymphoid Leukemia Protein/genetics MH - *Phenotype MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics/pathology MH - *Translocation, Genetic OTO - NOTNLM OT - copy number OT - mixed phenotype acute leukemia/lymphoma OT - pediatric lymphoblastic lymphoma OT - translocation EDAT- 2018/12/24 06:00 MHDA- 2019/05/21 06:00 CRDT- 2018/12/23 06:00 PHST- 2018/09/02 00:00 [received] PHST- 2018/12/18 00:00 [revised] PHST- 2018/12/18 00:00 [accepted] PHST- 2018/12/24 06:00 [pubmed] PHST- 2019/05/21 06:00 [medline] PHST- 2018/12/23 06:00 [entrez] AID - 10.1002/gcc.22726 [doi] PST - ppublish SO - Genes Chromosomes Cancer. 2019 Jun;58(6):365-372. doi: 10.1002/gcc.22726. Epub 2019 Jan 21.