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PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.


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.

SUBMITTER: Gu Z 

PROVIDER: S-EPMC6525306 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.

Gu Zhaohui Z   Churchman Michelle L ML   Roberts Kathryn G KG   Moore Ian I   Zhou Xin X   Nakitandwe Joy J   Hagiwara Kohei K   Pelletier Stephane S   Gingras Sebastien S   Berns Hartmut H   Payne-Turner Debbie D   Hill Ashley A   Iacobucci Ilaria I   Shi Lei L   Pounds Stanley S   Cheng Cheng C   Pei Deqing D   Qu Chunxu C   Newman Scott S   Devidas Meenakshi M   Dai Yunfeng Y   Reshmi Shalini C SC   Gastier-Foster Julie J   Raetz Elizabeth A EA   Borowitz Michael J MJ   Wood Brent L BL   Carroll William L WL   Zweidler-McKay Patrick A PA   Rabin Karen R KR   Mattano Leonard A LA   Maloney Kelly W KW   Rambaldi Alessandro A   Spinelli Orietta O   Radich Jerald P JP   Minden Mark D MD   Rowe Jacob M JM   Luger Selina S   Litzow Mark R MR   Tallman Martin S MS   Racevskis Janis J   Zhang Yanming Y   Bhatia Ravi R   Kohlschmidt Jessica J   Mrózek Krzysztof K   Bloomfield Clara D CD   Stock Wendy W   Kornblau Steven S   Kantarjian Hagop M HM   Konopleva Marina M   Evans Williams E WE   Jeha Sima S   Pui Ching-Hon CH   Yang Jun J   Paietta Elisabeth E   Downing James R JR   Relling Mary V MV   Zhang Jinghui J   Loh Mignon L ML   Hunger Stephen P SP   Mullighan Charles G CG  

Nature genetics 20190114 2


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  ...[more]

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