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

被引：16

作者：

Takeda, June ^{[1
]}

Yoshida, Kenichi ^{[1
]}

Nakagawa, Masahiro M. ^{[1
]}

Nannya, Yasuhito ^{[1
,2
]}

Yoda, Akinori ^{[1
]}

Saiki, Ryunosuke ^{[1
]}

Ochi, Yotaro ^{[1
]}

Zhao, Lanying ^{[3
]}

Okuda, Rurika ^{[1
]}

Qi, Xingxing ^{[1
]}

Mori, Takuto ^{[1
]}

Kon, Ayana ^{[1
]}

Chiba, Kenichi ^{[4
]}

Tanaka, Hiroko ^{[5
]}

Shiraishi, Yuichi ^{[4
]}

Kuo, Ming-Chung ^{[6
]}

Kerr, Cassandra M. ^{[7
]}

Nagata, Yasunobu ^{[7
]}

Morishita, Daisuke ^{[8
]}

Hiramoto, Nobuhiro ^{[9
]}

Hangaishi, Akira ^{[10
]}

Nakazawa, Hideyuki ^{[11
]}

Ishiyama, Ken ^{[12
]}

Miyano, Satoru ^{[5
]}

Chiba, Shigeru ^{[13
]}

Miyazaki, Yasushi ^{[14
,15
]}

Kitano, Toshiyuki ^{[16
]}

Usuki, Kensuke ^{[10
]}

Sezaki, Nobuo ^{[17
]}

Tsurumi, Hisashi ^{[18
]}

Miyawaki, Shuichi ^{[19
]}

Maciejewski, Jaroslaw P. ^{[7
]}

Ishikawa, Takayuki ^{[9
]}

Ohyashiki, Kazuma ^{[20
]}

Ganser, Arnold ^{[21
]}

Heuser, Michael ^{[21
]}

Thol, Felicitas ^{[21
]}

Shih, Lee-Yung ^{[6
]}

Takaori-Kondo, Akifumi ^{[22
]}

Makishima, Hideki ^{[1
]}

Ogawa, Seishi ^{[1
,3
,23
,24
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto, Japan

[2] Univ Tokyo, Inst Med Sci, Div Hematopoiet Dis Control, Tokyo, Japan

[3] Kyoto Univ, Inst Adv Study Human Biol WPI ASHBi, Kyoto, Japan

[4] Natl Canc Ctr, Div Genome Anal Platform Dev, Tokyo, Japan

[5] Tokyo Med & Dent Univ, M&D Data Sci Ctr, Tokyo, Japan

[6] Chang Gung Univ, Chang Gung Mem Hosp Linkou, Dept Internal Med cine, Div Hematol Oncol, Linkou, Taoyuan, Taiwan

[7] Cleveland Clin, Taussig Canc Inst, Dept Translat Hematol & Oncol ogy Res, Cleveland, OH USA

[8] Chordia Therapeut Inc, Kanagawa, Japan

[9] Kobe City Med Ctr Gen Hosp, Dept Hematol, Kobe, Japan

[10] NTT Med Ctr Tokyo, Dept Hematol, Tokyo, Japan

[11] Shinshu Univ Hosp, Dept Hematol, Matsumoto, Japan

[12] Kanazawa Univ, Dept Hematol, Kanazawa, Japan

[13] Univ Tsukuba, Fac Med, Dept Hematol, Tsukuba, Japan

[14] Nagasaki Univ, Atom Bomb Dis Inst, Dept Hematol, Nagasaki, Japan

[15] Japan Adult Leukemia Study Grp, Nagoya, Japan

[16] Kitano Hosp, Tazuke Kofukai Med Res Inst, Dept Hematol, Osaka, Japan

[17] Chugoku Cent Hosp, Dept Hematol, Hiroshima, Japan

[18] Gifu Univ, Dept Hematol, Gifu, Japan

[19] Tokyo Metropolitan Oht suka Hosp, Div Hematol, Tokyo, Japan

[20] Tokyo Med cal Univ, Dept Hematol, Tokyo, Japan

[21] Hannover Med Sch, Hannover, Germany

[22] Kyoto Univ, Grad Sch Med, Dept Hematol Oncol, Kyoto, Japan

[23] Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden

[24] Kyoto Univ, Pathol & Tumor Biol, Yoshida Konoe Cho, Sakyo Ku, Kyoto 6068501, Japan

来源：

BLOOD CANCER DISCOVERY | 2022年 / 3卷 / 05期

基金：

日本学术振兴会;

关键词：

ACUTE MYELOID-LEUKEMIA; WORLD-HEALTH-ORGANIZATION; CELL-LINE; ERYTHROPOIETIN RECEPTOR; MOUSE MODEL; CLASSIFICATION; MUTATIONS; DISTINCT; OVEREXPRESSION; EXPRESSION;

D O I：

10.1158/2643-3230.BCD-21-0192

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 amplifi cations involving EPOR/JAK2 in TP53-mutated cases, particularly those having > 80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompa-nied by gains and amplifi cations of ERG/ ETS2 and associated with a very poor prognosis, even com-pared 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, amplifi cations, 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.

引用

页码：410 / 427

页数：18

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