The genomic landscape of hypodiploid acute lymphoblastic leukemia
Linda Holmfeldt,Lei Wei,Ernesto Diaz-Flores,Michael Walsh,Jinghui Zhang,Li Ding,Debbie Payne-Turner,Michelle L. Churchman,Anna Andersson,Shann Ching Chen,Kelly McCastlain,Jared Becksfort,Jing Ma,Gang Wu,Samir Patel,Susan L. Heatley,Letha A. Phillips,Guangchun Song,John Easton,Matthew Parker,Xiang Chen,Michael Rusch,Kristy Boggs,Bhavin Vadodaria,Erin Hedlund,Christina D. Drenberg,Sharyn D. Baker,Deqing Pei,Cheng Cheng,Robert Huether,Charles Lu,Robert S. Fulton,Lucinda Fulton,Yashodhan Tabib,David J. Dooling,Kerri Ochoa,Mark D. Minden,Ian D. Lewis,L. Bik To,Paula Marlton,Andrew W. Roberts,Gordana Raca,Wendy Stock,Geoffrey Neale,Hans G. Drexler,Ross A. Dickins,David W. Ellison,Sheila A. Shurtleff,Ching-Hon Pui,Raul C. Ribeiro,Meenakshi Devidas,Andrew J. Carroll,Nyla A. Heerema,Brent L. Wood,Michael J. Borowitz,Julie M. Gastier-Foster,Julie M. Gastier-Foster,Susana C. Raimondi,Elaine R. Mardis,Richard K. Wilson,James R. Downing,Stephen P. Hunger,Mignon L. Loh,Charles G. Mullighan +63 more
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TLDR
Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.Abstract:
The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.read more
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Signatures of mutational processes in human cancer
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TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
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The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia
Daniel A. Arber,Attilio Orazi,Robert P. Hasserjian,Jürgen Thiele,Michael J. Borowitz,Michelle M. Le Beau,Clara D. Bloomfield,Mario Cazzola,James W. Vardiman +8 more
TL;DR: The 2016 edition of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition.
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The landscape of genomic alterations across childhood cancers
Susanne Gröbner,Barbara C. Worst,Joachim Weischenfeldt,Joachim Weischenfeldt,Ivo Buchhalter,Kortine Kleinheinz,Vasilisa A. Rudneva,Pascal Johann,Gnana Prakash Balasubramanian,Maia Segura-Wang,Sebastian Brabetz,Sebastian Bender,Barbara Hutter,Dominik Sturm,Elke Pfaff,Daniel Hübschmann,Gideon Zipprich,Michael Heinold,Michael Heinold,Jürgen Eils,Christian Lawerenz,Serap Erkek,Sander Lambo,Sebastian M. Waszak,Claudia Blattmann,Arndt Borkhardt,Arndt Borkhardt,Michaela Kuhlen,Michaela Kuhlen,Angelika Eggert,Angelika Eggert,Simone Fulda,Manfred Gessler,Jenny Wegert,Roland Kappler,Roland Kappler,Daniel Baumhoer,Stefan Burdach,Stefan Burdach,Renate Kirschner-Schwabe,Renate Kirschner-Schwabe,Udo Kontny,Andreas E. Kulozik,Andreas E. Kulozik,Dietmar R. Lohmann,Simone Hettmer,Cornelia Eckert,Cornelia Eckert,Stefan S. Bielack,Michaela Nathrath,Michaela Nathrath,Charlotte M. Niemeyer,Charlotte M. Niemeyer,Gunther Richter,Gunther Richter,Johannes H. Schulte,Johannes H. Schulte,Reiner Siebert,Frank Westermann,Jan J. Molenaar,Gilles Vassal,Hendrik Witt,Peter Lichter,Ursula Weber,Roland Eils,Roland Eils,Andrey Korshunov,Olaf Witt,Stefan Pfister,Guido Reifenberger,J Felsberg,Christof von Kalle,Manfred Schmidt,Cynthia Bartholomä,Michael Taylor,David T. W. Jones,Natalie Jäger,Korbel Jo,Adrian M. Stütz,Tobias Rausch,Bernhard Radlwimmer,Marie-Laure Yaspo,Hans Lehrach,Hans-Jörg Warnatz,Pablo Landgraf,Benedikt Brors,Marc Zapatka,Marc Zapatka,Susanne Wagner,Susanne Wagner,Andrea Haake,Julia Richter,Gesine Richter,Gesine Richter,Chris Lawerenz,Jules Kerssemakers,Christina Jaeger-Schmidt,Ingrid Scholz,Anke K. Bergmann,Christoph Borst,Birgit Burkhardt,Alexander Claviez,Martin Dreyling,Martin Dreyling,Sonja Eberth,Hermann Einsele,Norbert Frickhofen,Siegfried Haas,Martin-Leo Hansmann,Dennis Karsch,Michael Kneba,Jasmin Lisfeld,Luisa Mantovani-Löffler,Marius Rohde,German Ott,Christina Stadler,Peter Staib,Stephan Stilgenbauer,Lorenz Trümper,Thorsten Zenz,Dieter Kube,Ralf Küppers,Marc A. Weniger,Michael Hummel,Wolfram Klapper,Ulrike Kostezka,Dido Lenze,Peter Möller,Andreas Rosenwald,Monika Szczepanowski,Ole Ammerpohl,Sietse M. Aukema,Vera Binder,Jessica I. Hoell,Ellen Leich,Cristina López,Inga Nagel,Jordan Pischimariov,Philip Rosenstiel,Markus Schilhabel,Stefan Schreiber,Inga Vater,Rabea Wagener,Stephan H. Bernhart,Hans Binder,Gero Doose,Steve Hoffmann,Lydia Hopp,Helene Kretzmer,Markus Kreuz,David Langenberger,Markus Loeffler,Maciej Rosolowski,Matthias Schlesner,Peter F. Stadler,Stephanie Sungalee,Christian P. Kratz,Cornelis M. van Tilburg,Christof M. Kramm,Gudrun Fleischhack,Gudrun Fleischhack,Uta Dirksen,Stefan Rutkowski,Michael C. Frühwald,Katja von Hoff,Stephan Wolf,Thomas Klingebiel,Thomas Klingebiel,Ewa Koscielniak,Jan Koster,Adam C. Resnick,Jinghui Zhang,Yanling Liu,Xin Zhou,Angela J. Waanders,Danny A. Zwijnenburg,Pichai Raman,Ursula D. Weber,Paul A. Northcott,Kristian W. Pajtler,Marcel Kool,Rosario M. Piro,Jan O. Korbel,David T.W. Jones,Lukas Chavez,Stefan M. Pfister +185 more
TL;DR: The data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
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