| Literature DB >> 30643249 |
Zhaohui Gu1, Michelle L Churchman1, Kathryn G Roberts1, Ian Moore1, Xin Zhou2, Joy Nakitandwe1, Kohei Hagiwara2, Stephane Pelletier3, Sebastien Gingras4, Hartmut Berns5, Debbie Payne-Turner1, Ashley Hill1, Ilaria Iacobucci1, Lei Shi6, Stanley Pounds6, Cheng Cheng6, Deqing Pei6, Chunxu Qu1, Scott Newman2, Meenakshi Devidas7, Yunfeng Dai7, Shalini C Reshmi8, Julie Gastier-Foster8, Elizabeth A Raetz9, Michael J Borowitz10, Brent L Wood11, William L Carroll12, Patrick A Zweidler-McKay13, Karen R Rabin14, Leonard A Mattano15, Kelly W Maloney16, Alessandro Rambaldi17, Orietta Spinelli17, Jerald P Radich18, Mark D Minden19, Jacob M Rowe20, Selina Luger21, Mark R Litzow22, Martin S Tallman23, Janis Racevskis24, Yanming Zhang25, Ravi Bhatia26, Jessica Kohlschmidt27, Krzysztof Mrózek27, Clara D Bloomfield27, Wendy Stock28, Steven Kornblau29, Hagop M Kantarjian29, Marina Konopleva29, Williams E Evans30, Sima Jeha31, Ching-Hon Pui31, Jun Yang30, Elisabeth Paietta24, James R Downing1, Mary V Relling30, Jinghui Zhang2, Mignon L Loh32, Stephen P Hunger33, Charles G Mullighan34.
Abstract
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); 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.Entities:
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Year: 2019 PMID： 30643249 PMCID： PMC6525306 DOI： 10.1038/s41588-018-0315-5
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330