Amplified <i>EPOR</i>/<i>JAK2</i> Genes Define a Unique Subtype of Acute Erythroid Leukemia-Reference-Cited by-同舟云学术

Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

Published:2022-07-14 Issue:5 Volume:3 Page:410-427
ISSN:2643-3230
Container-title:Blood Cancer Discovery
language:en
Short-container-title:

Author:

Takeda June¹^ORCID,Yoshida Kenichi¹^ORCID,Nakagawa Masahiro M.¹^ORCID,Nannya Yasuhito¹²^ORCID,Yoda Akinori¹^ORCID,Saiki Ryunosuke¹^ORCID,Ochi Yotaro¹^ORCID,Zhao Lanying³^ORCID,Okuda Rurika¹^ORCID,Qi Xingxing¹^ORCID,Mori Takuto¹^ORCID,Kon Ayana¹^ORCID,Chiba Kenichi⁴^ORCID,Tanaka Hiroko⁵^ORCID,Shiraishi Yuichi⁴^ORCID,Kuo Ming-Chung⁶^ORCID,Kerr Cassandra M.⁷^ORCID,Nagata Yasunobu⁷^ORCID,Morishita Daisuke⁸^ORCID,Hiramoto Nobuhiro⁹^ORCID,Hangaishi Akira¹⁰^ORCID,Nakazawa Hideyuki¹¹^ORCID,Ishiyama Ken¹²^ORCID,Miyano Satoru⁵^ORCID,Chiba Shigeru¹³^ORCID,Miyazaki Yasushi¹⁴¹⁵^ORCID,Kitano Toshiyuki¹⁶^ORCID,Usuki Kensuke¹⁰^ORCID,Sezaki Nobuo¹⁷^ORCID,Tsurumi Hisashi¹⁸^ORCID,Miyawaki Shuichi¹⁹,Maciejewski Jaroslaw P.⁷^ORCID,Ishikawa Takayuki⁹^ORCID,Ohyashiki Kazuma²⁰,Ganser Arnold²¹^ORCID,Heuser Michael²¹^ORCID,Thol Felicitas²¹^ORCID,Shih Lee-Yung⁶^ORCID,Takaori-Kondo Akifumi²²^ORCID,Makishima Hideki¹^ORCID,Ogawa Seishi¹³²³^ORCID

Affiliation:

1. 1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

2. 2Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

3. 3Institute for the Advanced Study of Human Biology (WPI ASHBi), Kyoto University, Kyoto, Japan.

4. 4Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.

5. 5M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan.

6. 6Division of Hematology−Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University, Taoyuan, Taiwan.

7. 7Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.

8. 8Chordia Therapeutics Inc., Kanagawa, Japan.

9. 9Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.

10. 10Department of Hematology, NTT Medical Centre Tokyo, Tokyo, Japan.

11. 11Department of Hematology, Shinshu University Hospital, Matsumoto, Japan.

12. 12Department of Hematology, Kanazawa University, Kanazawa, Japan.

13. 13Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

14. 14Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

15. 15Japan Adult Leukemia Study Group, Japan.

16. 16Department of Hematology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan.

17. 17Department of Hematology, Chugoku Central Hospital, Hiroshima, Japan.

18. 18Department of Hematology, Gifu University, Gifu, Japan.

19. 19Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.

20. 20Department of Hematology, Tokyo Medical University, Tokyo, Japan.

21. 21Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

22. 22Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

23. 23Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.

Abstract

Abstract Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL. Significance: This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369

Funder

Japan Agency for Medical Research and Development

Ministry of Education, Culture, Sports, Science and Technology

Japan Society for the Promotion of Science

Publisher

American Association for Cancer Research (AACR)

Subject

General Medicine

Link

https://aacrjournals.org/bloodcancerdiscov/article-pdf/doi/10.1158/2643-3230.BCD-21-0192/3180420/bcd-21-0192.pdf

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