Targeting IRAK1 as a Therapeutic Approach for Myelodysplastic Syndrome

被引：193

作者：

Rhyasen, Garrett W. ^{[1
,2
]}

Bolanos, Lyndsey ^{[1
,2
]}

Fang, Jing ^{[1
]}

Jerez, Andres ^{[3
]}

Wunderlich, Mark ^{[1
]}

Rigolino, Carmela ^{[4
]}

Mathews, Lesley ^{[6
]}

Ferrer, Marc ^{[6
]}

Southall, Noel ^{[6
]}

Guha, Rajarshi ^{[6
]}

Keller, Jonathan ^{[6
]}

Thomas, Craig ^{[6
]}

Beverly, Levi J. ^{[7
]}

Cortelezzi, Agostino ^{[8
]}

Oliva, Esther N. ^{[5
]}

Cuzzola, Maria ^{[4
]}

Maciejewski, Jaroslaw P. ^{[3
]}

Mulloy, James C. ^{[1
]}

Starczynowski, Daniel T. ^{[1
,2
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[2] Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45267 USA

[3] Cleveland Clin, Taussig Canc Inst, Dept Translat Hematol & Oncol Res, Cleveland, OH 44195 USA

[4] Azienda Osped Bianchi Melacrino Morelli, Bone Marrow Transplant Unit, I-89100 Reggio Di Calabria, Italy

[5] Azienda Osped Bianchi Melacrino Morelli, Hematol Unit, I-89100 Reggio Di Calabria, Italy

[6] NHGRI, NIH Chem Genom Ctr, NIH, Rockville, MD 20850 USA

[7] Univ Louisville, Div Hematol & Oncol, Dept Med, James Graham Brown Canc Ctr, Louisville, KY 40202 USA

[8] Univ Milan, Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Hematol, I-20122 Milan, Italy

来源：

CANCER CELL | 2013年 / 24卷 / 01期

基金：

美国国家卫生研究院;

关键词：

NF-KAPPA-B; ACUTE MYELOID-LEUKEMIA; GENE-EXPRESSION; ENRICHMENT ANALYSIS; CELL-LINE; STEM; IDENTIFICATION; INHIBITION; SIGNATURE; MIR-146A;

D O I：

10.1016/j.ccr.2013.05.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Myelodysplastic syndromes (MDSs) arise from a defective hematopoietic stem/progenitor cell. Consequently, there is an urgent need to develop targeted therapies capable of eliminating the MDS-initiating clones. We identified that IRAK1, an immune-modulating kinase, is overexpressed and hyperactivated in MDSs. MDS clones treated with a small molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-kappa B inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is detrimental to MDS cells, while sparing normal CD34(+) cells. Based on an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that cotreatment more effectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDSs.

引用

页码：90 / 104

页数：15

共 45 条

[1]

Bar Merav, 2008, Transl Oncogenomics, V3, P137

[2]

Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS [J].

Barreyro, Laura ;

Will, Britta ;

Bartholdy, Boris ;

Zhou, Li ;

Todorova, Tihomira I. ;

Stanley, Robert F. ;

Ben-Neriah, Susana ;

Montagna, Cristina ;

Parekh, Samir ;

Pellagatti, Andrea ;

Boultwood, Jacqueline ;

Paietta, Elisabeth ;

Ketterling, Rhett P. ;

Cripe, Larry ;

Fernandez, Hugo F. ;

Greenberg, Peter L. ;

Tallman, Martin S. ;

Steidl, Christian ;

Mitsiades, Constantine S. ;

Verma, Amit ;

Steidl, Ulrich .

BLOOD, 2012, 120 (06) :1290-1298

[3]

miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice [J].

Boldin, Mark P. ;

Taganov, Konstantin D. ;

Rao, Dinesh S. ;

Yang, Lili ;

Zhao, Jimmy L. ;

Kalwani, Manorama ;

Garcia-Flores, Yvette ;

Luong, Mui ;

Devrekanli, Asli ;

Xu, Jessica ;

Sun, Guizhen ;

Tay, Jia ;

Linsley, Peter S. ;

Baltimore, David .

JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 208 (06) :1189-1201

[4]

NF-κB as a potential therapeutic target in myelodysplastic syndromes and acute myeloid leukemia [J].

Breccia, Massimo ;

Alimena, Giuliana .

EXPERT OPINION ON THERAPEUTIC TARGETS, 2010, 14 (11) :1157-1176

[5]

Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression [J].

Camos, Mireia ;

Esteve, Jordi ;

Jares, Pedro ;

Colomer, Dolors ;

Rozman, Maria ;

Villamor, Neus ;

Costa, Dolors ;

Carrio, Ana ;

Nomdedeu, Josep ;

Montserrat, Emili ;

Campo, Elias .

CANCER RESEARCH, 2006, 66 (14) :6947-6954

[6]

Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities [J].

Chen, GB ;

Zeng, WH ;

Miyazato, A ;

Billings, E ;

Maciejewski, JP ;

Kajigaya, S ;

Sloand, EM ;

Young, NS .

BLOOD, 2004, 104 (13) :4210-4218

[7]

ToppGene Suite for gene list enrichment analysis and candidate gene prioritization [J].

Chen, Jing ;

Bardes, Eric E. ;

Aronow, Bruce J. ;

Jegga, Anil G. .

NUCLEIC ACIDS RESEARCH, 2009, 37 :W305-W311

[8]

Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and Toll-like receptor-mediated NF-κB activation [J].

Conze, Dietrich B. ;

Wu, Chuan-Jin ;

Thomas, James A. ;

Landstrom, Allison ;

Ashwell, Jonathan D. .

MOLECULAR AND CELLULAR BIOLOGY, 2008, 28 (10) :3538-3547

[9]

Myelodysplastic syndromes: the complexity of stem-cell diseases [J].

Corey, Seth J. ;

Minden, Mark D. ;

Barber, Dwayne L. ;

Kantarjian, Hagop ;

Wang, Jean C. Y. ;

Schimmer, Aaron D. .

NATURE REVIEWS CANCER, 2007, 7 (02) :118-129

[10]

Durand-Reville T., 2008, U.S. patent, Patent No. [WO/2008/030579, 2008030579]

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