Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia

被引：51

作者：

Kadono, Moe ^{[1
,2
,3
]}

Kanai, Akinori ^{[1
,2
]}

Nagamachi, Akiko ^{[1
,2
]}

Shinriki, Satoru ^{[4
,5
]}

Kawata, Jin ^{[5
]}

Iwato, Koji ^{[6
,7
]}

Kyo, Taiichi ^{[6
,7
]}

Oshima, Kumi ^{[3
]}

Yokoyama, Akihiko ^{[8
]}

Kawamura, Takeshi ^{[9
]}

Nagase, Reina ^{[10
]}

Inoue, Daichi ^{[10
]}

Kitamura, Toshio ^{[10
]}

Inaba, Toshiya ^{[1
,2
]}

Ichinohe, Tatsuo ^{[3
]}

Matsui, Hirotaka ^{[1
,2
,4
,5
]}

机构：

[1] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Mol Oncol, Hiroshima 7848553, Japan

[2] Hiroshima Univ, Res Inst Radiat Biol & Med, Leukemia Program Project, Hiroshima 7848553, Japan

[3] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Hematol & Oncol, Hiroshima 7848553, Japan

[4] Kumamoto Univ, Grad Sch Med Sci, Dept Mol Lab Med, Kumamoto 8608556, Japan

[5] Kumamoto Univ Hosp, Cent Clin Lab, Kumamoto, Japan

[6] Hiroshima Red Cross Hosp, Dept Hematol, Hiroshima, Japan

[7] Atom Bomb Survivors Hosp, Hiroshima, Japan

[8] Kyoto Univ, Grad Sch Med, Med Innovat Ctr, Lab Malignancy Control Res, Kyoto, Japan

[9] Univ Tokyo, Dept Mol Biol & Med, LSBM, RCAST, Tokyo, Japan

[10] Univ Tokyo, Inst Med Sci, Div Cellular Therapy, Tokyo, Japan

来源：

EXPERIMENTAL HEMATOLOGY | 2016年 / 44卷 / 08期

关键词：

RIG-I; RNA; ACTIVATION; EXPRESSION; GENE; P53; IDENTIFICATION; INHIBITION; REGIONS; GROWTH;

D O I：

10.1016/j.exphem.2016.04.017

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The DDX41 gene, encoding a DEAD-box type ATP-dependent RNA helicase, is rarely but reproducibly mutated in myeloid diseases. The acquired mutation in DDX41 is highly concentrated at c.G1574A (p.R525H) in the conserved motif VI located at the C-terminus of the helicase core domain where ATP interacts and is hydrolyzed. Therefore, it is likely that the p.R525H mutation perturbs ATPase activity in a dominant-negative manner. In this study, we screened for the DDX41 mutation of CD34-positive tumor cells based on mRNA sequencing and identified the p.R525H mutation in three cases among 23 patients. Intriguingly, these patients commonly exhibited acute myeloid leukemia (AML) with peripheral blood cytopenias and low blast counts, suggesting that the mutation inhibits the growth and differentiation of hematopoietic cells. Data from cord blood cells and leukemia cell lines suggest a role for DDX41 in preribosomal RNA processing, in which the expression of the p.R525H mutant causes a certain ribosomopathy phenotype in hematopoietic cells by suppressing MDM2-mediated RB degradation, thus triggering the inhibition of E2F activity. This study uncovered a pathogenic role of p.R525H DDX41 in the slow growth rate of tumor cells. Age-dependent epigenetic alterations or other somatic changes might collaborate with the mutation to cause AML. Copyright (C) 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.

引用

页码：745 / 754

页数：10

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[1] Abstrakt interacts with and regulates the expression of sorting Nexin-2 [J].