Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival

被引:72
作者
Hunter, MG
Avalos, BR
机构
[1] Ohio State Univ, Mol Cellular & Dev Biol Program, Arthur G James Canc Hosp & Res Inst, Columbus, OH 43210 USA
[2] Ohio State Univ, Bone Marrow Transplantat Program, Arthur G James Canc Hosp & Res Inst, Columbus, OH 43210 USA
关键词
D O I
10.1182/blood.V95.6.2132
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
patients with severe congenital neutropenia (SCN) are at increased risk for the development of acute myelogenous leukemia (AML), In the subset of patients with SCN that progresses to AML, acquired mutations in the receptor for granulocyte colony-stimulating factor (G-CSF) have been detected that result in the expression of truncated forms of the G-CSF receptor (G-CSFR) protein. G-CSFR truncation mutants from these patients transduce hyperproliferative growth responses, In this paper, we show that the most frequently isolated mutant G-CSFR form from patients with SCN/AML (Delta 716) confers resistance to apoptosis and prolongs cell survival through a mechanism involving AM, a downstream target of PI3-kinase. G-CSF stimulation of cells expressing the G-CSFR truncation mutant induces sustained activation of Akt and prolonged phosphorylation of the pro-apoptotic protein Bad, resulting in enhanced cell survival. Extension of cell survival allowing for sufficient time for the acquisition of additional oncogenic events may represent an important mechanism by which G-CSFR mutations contribute to leukemogenesis, These data provide further insight Into the pathophysiologic contribution of G-CSFR mutations to AML, (C) 2000 by The American Society of Hematology.
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收藏
页码:2132 / 2137
页数:6
相关论文
共 29 条
[1]   Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase [J].
Ahmed, NN ;
Grimes, HL ;
Bellacosa, A ;
Chan, TO ;
Tsichlis, PN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (08) :3627-3632
[2]   Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B alpha [J].
Alessi, DR ;
James, SR ;
Downes, CP ;
Holmes, AB ;
Gaffney, PRJ ;
Reese, CB ;
Cohen, P .
CURRENT BIOLOGY, 1997, 7 (04) :261-269
[3]  
BEGLEY CG, 1988, EXP HEMATOL, V16, P71
[4]   Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery [J].
Datta, SR ;
Dudek, H ;
Tao, X ;
Masters, S ;
Fu, HA ;
Gotoh, Y ;
Greenberg, ME .
CELL, 1997, 91 (02) :231-241
[5]  
delPeso L, 1997, SCIENCE, V278, P687
[6]  
DEMETRI GD, 1991, BLOOD, V78, P2791
[7]   MUTATIONS IN THE GENE FOR THE GRANULOCYTE COLONY-STIMULATING-FACTOR RECEPTOR IN PATIENTS WITH ACUTE MYELOID-LEUKEMIA PRECEDED BY SEVERE CONGENITAL NEUTROPENIA [J].
DONG, F ;
BRYNES, RK ;
TIDOW, N ;
WELTE, K ;
LOWENBERG, B ;
TOUW, IP .
NEW ENGLAND JOURNAL OF MEDICINE, 1995, 333 (08) :487-493
[8]   IDENTIFICATION OF A NONSENSE MUTATION IN THE GRANULOCYTE-COLONY-STIMULATING FACTOR-RECEPTOR IN SEVERE CONGENITAL NEUTROPENIA [J].
DONG, F ;
HOEFSLOOT, LH ;
SCHELEN, AM ;
BROEDERS, LCAM ;
MEIJER, Y ;
VEERMAN, AJP ;
TOUW, IP ;
LOWENBERG, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (10) :4480-4484
[9]   Akt, a target of phosphatidylinositol 3-kinase, inhibits apoptosis in a differentiating neuronal cell line [J].
Eves, EM ;
Xiong, W ;
Bellacosa, A ;
Kennedy, SG ;
Tsichlis, PN ;
Rosner, MR ;
Hay, N .
MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (04) :2143-2152
[10]   THE PROTEIN-KINASE ENCODED BY THE AKT PROTOONCOGENE IS A TARGET OF THE PDGF-ACTIVATED PHOSPHATIDYLINOSITOL 3-KINASE [J].
FRANKE, TF ;
YANG, SI ;
CHAN, TO ;
DATTA, K ;
KAZLAUSKAS, A ;
MORRISON, DK ;
KAPLAN, DR ;
TSICHLIS, PN .
CELL, 1995, 81 (05) :727-736