Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia

Masafumi Seki; Shunsuke Kimura; Tomoya Isobe; Kenichi Yoshida; Hiroo Ueno; Yaeko Nakajima-Takagi; Changshan Wang; Lin Lin; Ayana Kon; Hiromichi Suzuki; Yusuke Shiozawa; Keisuke Kataoka; Yoichi Fujii; Yuichi Shiraishi; Kenichi Chiba; Hiroko Tanaka; Teppei Shimamura; Kyoko Masuda; Hiroshi Kawamoto; Kentaro Ohki; Motohiro Kato; Yuki Arakawa; Katsuyoshi Koh; Ryoji Hanada; Hiroshi Moritake; Masaharu Akiyama; Ryoji Kobayashi; Takao Deguchi; Yoshiko Hashii; Toshihiko Imamura; Atsushi Sato; Nobutaka Kiyokawa; Akira Oka; Yasuhide Hayashi; Masatoshi Takagi; Atsushi Manabe; Akira Ohara; Keizo Horibe; Masashi Sanada; Atsushi Iwama; Hiroyuki Mano; Satoru Miyano; Seishi Ogawa; Junko Takita

doi:10.1038/ng.3900

Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia

Masafumi Seki, Shunsuke Kimura, Tomoya Isobe, Kenichi Yoshida, Hiroo Ueno, Yaeko Nakajima-Takagi, Changshan Wang, Lin Lin, Ayana Kon, Hiromichi Suzuki, Yusuke Shiozawa, Keisuke Kataoka, Yoichi Fujii, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Teppei Shimamura, Kyoko Masuda, Hiroshi Kawamoto, Kentaro OhkiMotohiro Kato, Yuki Arakawa, Katsuyoshi Koh, Ryoji Hanada, Hiroshi Moritake, Masaharu Akiyama, Ryoji Kobayashi, Takao Deguchi, Yoshiko Hashii, Toshihiko Imamura, Atsushi Sato, Nobutaka Kiyokawa, Akira Oka, Yasuhide Hayashi, Masatoshi Takagi, Atsushi Manabe, Akira Ohara, Keizo Horibe, Masashi Sanada, Atsushi Iwama, Hiroyuki Mano, Satoru Miyano, Seishi Ogawa, Junko Takita

International Center for Cell and Gene Therapy

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

97 Citations (Scopus)

Abstract

The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4 - CD8 -) or CD8 + single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.

Original language	English
Pages (from-to)	1274-1281
Number of pages	8
Journal	Nature Genetics
Volume	49
Issue number	8
DOIs	https://doi.org/10.1038/ng.3900
Publication status	Published - 01-08-2017

All Science Journal Classification (ASJC) codes

Genetics

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10.1038/ng.3900

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Seki, M., Kimura, S., Isobe, T., Yoshida, K., Ueno, H., Nakajima-Takagi, Y., Wang, C., Lin, L., Kon, A., Suzuki, H., Shiozawa, Y., Kataoka, K., Fujii, Y., Shiraishi, Y., Chiba, K., Tanaka, H., Shimamura, T., Masuda, K., Kawamoto, H., ... Takita, J. (2017). Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. Nature Genetics, 49(8), 1274-1281. https://doi.org/10.1038/ng.3900

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title = "Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia",

abstract = "The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4 - CD8 -) or CD8 + single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.",

author = "Masafumi Seki and Shunsuke Kimura and Tomoya Isobe and Kenichi Yoshida and Hiroo Ueno and Yaeko Nakajima-Takagi and Changshan Wang and Lin Lin and Ayana Kon and Hiromichi Suzuki and Yusuke Shiozawa and Keisuke Kataoka and Yoichi Fujii and Yuichi Shiraishi and Kenichi Chiba and Hiroko Tanaka and Teppei Shimamura and Kyoko Masuda and Hiroshi Kawamoto and Kentaro Ohki and Motohiro Kato and Yuki Arakawa and Katsuyoshi Koh and Ryoji Hanada and Hiroshi Moritake and Masaharu Akiyama and Ryoji Kobayashi and Takao Deguchi and Yoshiko Hashii and Toshihiko Imamura and Atsushi Sato and Nobutaka Kiyokawa and Akira Oka and Yasuhide Hayashi and Masatoshi Takagi and Atsushi Manabe and Akira Ohara and Keizo Horibe and Masashi Sanada and Atsushi Iwama and Hiroyuki Mano and Satoru Miyano and Seishi Ogawa and Junko Takita",

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Seki, M, Kimura, S, Isobe, T, Yoshida, K, Ueno, H, Nakajima-Takagi, Y, Wang, C, Lin, L, Kon, A, Suzuki, H, Shiozawa, Y, Kataoka, K, Fujii, Y, Shiraishi, Y, Chiba, K, Tanaka, H, Shimamura, T, Masuda, K, Kawamoto, H, Ohki, K, Kato, M, Arakawa, Y, Koh, K, Hanada, R, Moritake, H, Akiyama, M, Kobayashi, R, Deguchi, T, Hashii, Y, Imamura, T, Sato, A, Kiyokawa, N, Oka, A, Hayashi, Y, Takagi, M, Manabe, A, Ohara, A, Horibe, K, Sanada, M, Iwama, A, Mano, H, Miyano, S, Ogawa, S & Takita, J 2017, 'Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia', Nature Genetics, vol. 49, no. 8, pp. 1274-1281. https://doi.org/10.1038/ng.3900

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T1 - Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia

AU - Seki, Masafumi

AU - Kimura, Shunsuke

AU - Isobe, Tomoya

AU - Yoshida, Kenichi

AU - Ueno, Hiroo

AU - Nakajima-Takagi, Yaeko

AU - Wang, Changshan

AU - Lin, Lin

AU - Kon, Ayana

AU - Suzuki, Hiromichi

AU - Shiozawa, Yusuke

AU - Kataoka, Keisuke

AU - Fujii, Yoichi

AU - Shiraishi, Yuichi

AU - Chiba, Kenichi

AU - Tanaka, Hiroko

AU - Shimamura, Teppei

AU - Masuda, Kyoko

AU - Kawamoto, Hiroshi

AU - Ohki, Kentaro

AU - Kato, Motohiro

AU - Arakawa, Yuki

AU - Koh, Katsuyoshi

AU - Hanada, Ryoji

AU - Moritake, Hiroshi

AU - Akiyama, Masaharu

AU - Kobayashi, Ryoji

AU - Deguchi, Takao

AU - Hashii, Yoshiko

AU - Imamura, Toshihiko

AU - Sato, Atsushi

AU - Kiyokawa, Nobutaka

AU - Oka, Akira

AU - Hayashi, Yasuhide

AU - Takagi, Masatoshi

AU - Manabe, Atsushi

AU - Ohara, Akira

AU - Horibe, Keizo

AU - Sanada, Masashi

AU - Iwama, Atsushi

AU - Mano, Hiroyuki

AU - Miyano, Satoru

AU - Ogawa, Seishi

AU - Takita, Junko

PY - 2017/8/1

Y1 - 2017/8/1

N2 - The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4 - CD8 -) or CD8 + single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.

AB - The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4 - CD8 -) or CD8 + single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.

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JO - Nature Genetics

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Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia

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