NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

被引：42

作者：

Adamia, Sophia ^{[1
]}

Bar-Natan, Michal ^{[2
]}

Haibe-Kains, Benjamin ^{[3
]}

Pilarski, Patrick M. ^{[4
]}

Bach, Christian ^{[2
]}

Pevzner, Samuel ^{[5
,6
]}

Calimeri, Teresa ^{[1
,7
,8
]}

Avet-Loiseau, Herve ^{[9
]}

Lode, Laurence ^{[10
,11
]}

Verselis, Sigitas ^{[12
]}

Fox, Edward A. ^{[12
]}

Galinsky, Ilene ^{[13
]}

Mathews, Steven ^{[13
]}

Dagogo-Jack, Ibiayi ^{[14
]}

Wadleigh, Martha ^{[1
,13
]}

Steensma, David P. ^{[1
,13
]}

Motyckova, Gabriela ^{[1
,13
]}

Deangelo, Daniel J. ^{[1
,13
]}

Quackenbush, John ^{[1
]}

Tenen, Daniel G. ^{[2
]}

Stone, Richard M. ^{[1
,13
]}

Griffin, James D. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA

[2] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA

[3] Inst Rech Clin Montreal, Bioinformat & Computat Genom Lab, Montreal, PQ H2W 1R7, Canada

[4] Univ Alberta, Dept Comp Sci, Edmonton, AB, Canada

[5] Boston Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02118 USA

[6] Boston Univ, Sch Med, Dept Genet, Boston, MA 02118 USA

[7] Magna Graecia Univ Catanzaro, Catanzaro, Italy

[8] Tommaso Campanella Canc Ctr, Catanzaro, Italy

[9] Ctr Hosp Univ Rangueil, Univ Hosp, Unite Genom Myelome, Lab Unite Genom Myelome, Toulouse, France

[10] Univ Hosp, Hematol Lab, Nantes, France

[11] INSERM, U892, Nantes, France

[12] Dana Farber Canc Inst, Mol Diagnost Lab, Boston, MA 02215 USA

[13] Dana Farber Canc Inst, Adult Leukemia Program, Boston, MA 02215 USA

[14] Brigham & Womens Hosp, Boston, MA 02115 USA

来源：

BLOOD | 2014年 / 123卷 / 18期

基金：

美国国家卫生研究院;

关键词：

MUTATIONS; EXPRESSION; ISOFORM; VARIANT;

D O I：

10.1182/blood-2013-02-481507

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34(+) bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (> 70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics.

引用

页码：2816 / 2825

页数：10

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