PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia

Zhaohui Gu, Michelle L. Churchman, Kathryn G. Roberts, Ian Moore, Xin Zhou, Joy Nakitandwe, Kohei Hagiwara, Stephane Pelletier, Sebastien Gingras, Hartmut Berns, Debbie Payne-Turner, Ashley Hill, Ilaria Iacobucci, Lei Shi, Stanley Pounds, Cheng Cheng, Deqing Pei, Chunxu Qu, Scott Newman, Meenakshi DevidasYunfeng Dai, Shalini C. Reshmi, Julie Gastier-Foster, Elizabeth A. Raetz, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Patrick A. Zweidler-McKay, Karen R. Rabin, Leonard A. Mattano, Kelly W. Maloney, Alessandro Rambaldi, Orietta Spinelli, Jerald P. Radich, Mark D. Minden, Jacob M. Rowe, Selina Luger, Mark R. Litzow, Martin S. Tallman, Janis Racevskis, Yanming Zhang, Ravi Bhatia, Jessica Kohlschmidt, Krzysztof Mrózek, Clara D. Bloomfield, Wendy Stock, Steven Kornblau, Hagop M. Kantarjian, Marina Konopleva, Williams E. Evans, Sima Jeha, Ching Hon Pui, Jun Yang, Elisabeth Paietta, James R. Downing, Mary V. Relling, Jinghui Zhang, Mignon L. Loh, Stephen P. Hunger, Charles G. Mullighan

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)296-307
Number of pages12
JournalNature Genetics
Issue number2
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Genetics


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