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 M. Paietta, James R. Downing, Mary V. Relling, Jinghui Zhang, Mignon L. Loh, Stephen P. Hunger, Charles G. Mullighan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)296-307
Number of pages12
JournalNature Genetics
Volume51
Issue number2
DOIs
StatePublished - Feb 1 2019

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
PAX5 Transcription Factor
Mutation
Transcriptome
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Gu, Z., Churchman, M. L., Roberts, K. G., Moore, I., Zhou, X., Nakitandwe, J., ... Mullighan, C. G. (2019). PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nature Genetics, 51(2), 296-307. https://doi.org/10.1038/s41588-018-0315-5

PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. / Gu, Zhaohui; Churchman, Michelle L.; Roberts, Kathryn G.; Moore, Ian; Zhou, Xin; Nakitandwe, Joy; Hagiwara, Kohei; Pelletier, Stephane; Gingras, Sebastien; Berns, Hartmut; Payne-Turner, Debbie; Hill, Ashley; Iacobucci, Ilaria; Shi, Lei; Pounds, Stanley; Cheng, Cheng; Pei, Deqing; Qu, Chunxu; Newman, Scott; Devidas, Meenakshi; Dai, Yunfeng; Reshmi, Shalini C.; Gastier-Foster, Julie; Raetz, Elizabeth A.; Borowitz, Michael J.; Wood, Brent L.; Carroll, William L.; Zweidler-McKay, Patrick A.; Rabin, Karen R.; Mattano, Leonard A.; Maloney, Kelly W.; Rambaldi, Alessandro; Spinelli, Orietta; Radich, Jerald P.; Minden, Mark D.; Rowe, Jacob M.; Luger, Selina; Litzow, Mark R.; Tallman, Martin S.; Racevskis, Janis; Zhang, Yanming; Bhatia, Ravi; Kohlschmidt, Jessica; Mrózek, Krzysztof; Bloomfield, Clara D.; Stock, Wendy; Kornblau, Steven; Kantarjian, Hagop M.; Konopleva, Marina; Evans, Williams E.; Jeha, Sima; Pui, Ching Hon; Yang, Jun; Paietta, Elisabeth M.; Downing, James R.; Relling, Mary V.; Zhang, Jinghui; Loh, Mignon L.; Hunger, Stephen P.; Mullighan, Charles G.

In: Nature Genetics, Vol. 51, No. 2, 01.02.2019, p. 296-307.

Research output: Contribution to journalArticle

Gu, Z, Churchman, ML, Roberts, KG, Moore, I, Zhou, X, Nakitandwe, J, Hagiwara, K, Pelletier, S, Gingras, S, Berns, H, Payne-Turner, D, Hill, A, Iacobucci, I, Shi, L, Pounds, S, Cheng, C, Pei, D, Qu, C, Newman, S, Devidas, M, Dai, Y, Reshmi, SC, Gastier-Foster, J, Raetz, EA, Borowitz, MJ, Wood, BL, Carroll, WL, Zweidler-McKay, PA, Rabin, KR, Mattano, LA, Maloney, KW, Rambaldi, A, Spinelli, O, Radich, JP, Minden, MD, Rowe, JM, Luger, S, Litzow, MR, Tallman, MS, Racevskis, J, Zhang, Y, Bhatia, R, Kohlschmidt, J, Mrózek, K, Bloomfield, CD, Stock, W, Kornblau, S, Kantarjian, HM, Konopleva, M, Evans, WE, Jeha, S, Pui, CH, Yang, J, Paietta, EM, Downing, JR, Relling, MV, Zhang, J, Loh, ML, Hunger, SP & Mullighan, CG 2019, 'PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia', Nature Genetics, vol. 51, no. 2, pp. 296-307. https://doi.org/10.1038/s41588-018-0315-5
Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nature Genetics. 2019 Feb 1;51(2):296-307. https://doi.org/10.1038/s41588-018-0315-5
Gu, Zhaohui ; Churchman, Michelle L. ; Roberts, Kathryn G. ; Moore, Ian ; Zhou, Xin ; Nakitandwe, Joy ; Hagiwara, Kohei ; Pelletier, Stephane ; Gingras, Sebastien ; Berns, Hartmut ; Payne-Turner, Debbie ; Hill, Ashley ; Iacobucci, Ilaria ; Shi, Lei ; Pounds, Stanley ; Cheng, Cheng ; Pei, Deqing ; Qu, Chunxu ; Newman, Scott ; Devidas, Meenakshi ; Dai, Yunfeng ; Reshmi, Shalini C. ; Gastier-Foster, Julie ; Raetz, Elizabeth A. ; Borowitz, Michael J. ; Wood, Brent L. ; Carroll, William L. ; Zweidler-McKay, Patrick A. ; Rabin, Karen R. ; Mattano, Leonard A. ; Maloney, Kelly W. ; Rambaldi, Alessandro ; Spinelli, Orietta ; Radich, Jerald P. ; Minden, Mark D. ; Rowe, Jacob M. ; Luger, Selina ; Litzow, Mark R. ; Tallman, Martin S. ; Racevskis, Janis ; Zhang, Yanming ; Bhatia, Ravi ; Kohlschmidt, Jessica ; Mrózek, Krzysztof ; Bloomfield, Clara D. ; Stock, Wendy ; Kornblau, Steven ; Kantarjian, Hagop M. ; Konopleva, Marina ; Evans, Williams E. ; Jeha, Sima ; Pui, Ching Hon ; Yang, Jun ; Paietta, Elisabeth M. ; Downing, James R. ; Relling, Mary V. ; Zhang, Jinghui ; Loh, Mignon L. ; Hunger, Stephen P. ; Mullighan, Charles G. / PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. In: Nature Genetics. 2019 ; Vol. 51, No. 2. pp. 296-307.
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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.",
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AU - Gu, Zhaohui

AU - Churchman, Michelle L.

AU - Roberts, Kathryn G.

AU - Moore, Ian

AU - Zhou, Xin

AU - Nakitandwe, Joy

AU - Hagiwara, Kohei

AU - Pelletier, Stephane

AU - Gingras, Sebastien

AU - Berns, Hartmut

AU - Payne-Turner, Debbie

AU - Hill, Ashley

AU - Iacobucci, Ilaria

AU - Shi, Lei

AU - Pounds, Stanley

AU - Cheng, Cheng

AU - Pei, Deqing

AU - Qu, Chunxu

AU - Newman, Scott

AU - Devidas, Meenakshi

AU - Dai, Yunfeng

AU - Reshmi, Shalini C.

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AU - Borowitz, Michael J.

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AU - Carroll, William L.

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AU - Rabin, Karen R.

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AU - Maloney, Kelly W.

AU - Rambaldi, Alessandro

AU - Spinelli, Orietta

AU - Radich, Jerald P.

AU - Minden, Mark D.

AU - Rowe, Jacob M.

AU - Luger, Selina

AU - Litzow, Mark R.

AU - Tallman, Martin S.

AU - Racevskis, Janis

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AU - Bhatia, Ravi

AU - Kohlschmidt, Jessica

AU - Mrózek, Krzysztof

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AU - Evans, Williams E.

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AU - Yang, Jun

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AU - Downing, James R.

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N2 - 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.

AB - 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.

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