PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia

Yizhen Li; Takaya Moriyama; Satoshi Yoshimura; Xujie Zhao; Zhenhua Li; Xu Yang; Elisabeth Paietta; Mark R. Litzow; Marina Konopleva; Jiyang Yu; Hiroto Inaba; Raul C. Ribeiro; Ching Hon Pui; Jun J. Yang

doi:10.1126/sciadv.add6403

PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia

Yizhen Li, Takaya Moriyama, Satoshi Yoshimura, Xujie Zhao, Zhenhua Li, Xu Yang, Elisabeth Paietta, Mark R. Litzow, Marina Konopleva, Jiyang Yu, Hiroto Inaba, Raul C. Ribeiro, Ching Hon Pui, Jun J. Yang

Oncology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genomewide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19. Screening 1639 transcription factor genes, we then identified PAX5 as the key activator of CD58. ALL with the PAX5 P80R mutation also expressed the lowest level of CD58 among 20 ALL molecular subtypes in 1988 patients. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R, and the loss of CD58 abolished blinatumomab-induced T cell activation with global changes in transcriptomic/epigenomic program. In conclusion, we identified previously unidentified genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.

Original language	English (US)
Article number	add6403
Journal	Science Advances
Volume	8
Issue number	50
DOIs	https://doi.org/10.1126/sciadv.add6403
State	Published - 2022

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Li, Y., Moriyama, T., Yoshimura, S., Zhao, X., Li, Z., Yang, X., Paietta, E., Litzow, M. R., Konopleva, M., Yu, J., Inaba, H., Ribeiro, R. C., Pui, C. H., & Yang, J. J. (2022). PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia. Science Advances, 8(50), Article add6403. https://doi.org/10.1126/sciadv.add6403

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title = "PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia",

abstract = "Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genomewide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19. Screening 1639 transcription factor genes, we then identified PAX5 as the key activator of CD58. ALL with the PAX5 P80R mutation also expressed the lowest level of CD58 among 20 ALL molecular subtypes in 1988 patients. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R, and the loss of CD58 abolished blinatumomab-induced T cell activation with global changes in transcriptomic/epigenomic program. In conclusion, we identified previously unidentified genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.",

author = "Yizhen Li and Takaya Moriyama and Satoshi Yoshimura and Xujie Zhao and Zhenhua Li and Xu Yang and Elisabeth Paietta and Litzow, {Mark R.} and Marina Konopleva and Jiyang Yu and Hiroto Inaba and Ribeiro, {Raul C.} and Pui, {Ching Hon} and Yang, {Jun J.}",

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year = "2022",

doi = "10.1126/sciadv.add6403",

language = "English (US)",

volume = "8",

journal = "Science Advances",

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T1 - PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia

AU - Li, Yizhen

AU - Moriyama, Takaya

AU - Yoshimura, Satoshi

AU - Zhao, Xujie

AU - Li, Zhenhua

AU - Yang, Xu

AU - Paietta, Elisabeth

AU - Litzow, Mark R.

AU - Konopleva, Marina

AU - Yu, Jiyang

AU - Inaba, Hiroto

AU - Ribeiro, Raul C.

AU - Pui, Ching Hon

AU - Yang, Jun J.

PY - 2022

Y1 - 2022

N2 - Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genomewide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19. Screening 1639 transcription factor genes, we then identified PAX5 as the key activator of CD58. ALL with the PAX5 P80R mutation also expressed the lowest level of CD58 among 20 ALL molecular subtypes in 1988 patients. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R, and the loss of CD58 abolished blinatumomab-induced T cell activation with global changes in transcriptomic/epigenomic program. In conclusion, we identified previously unidentified genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.

AB - Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genomewide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19. Screening 1639 transcription factor genes, we then identified PAX5 as the key activator of CD58. ALL with the PAX5 P80R mutation also expressed the lowest level of CD58 among 20 ALL molecular subtypes in 1988 patients. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R, and the loss of CD58 abolished blinatumomab-induced T cell activation with global changes in transcriptomic/epigenomic program. In conclusion, we identified previously unidentified genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.

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PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia

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