Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

被引：208

作者：

McCubrey, J. A. ^{[1
]}

Steelman, L. S. ^{[1
]}

Abrams, S. L. ^{[1
]}

Bertrand, F. E. ^{[1
]}

Ludwig, D. E. ^{[2
]}

Baesecke, J. ^{[3
]}

Libra, M. ^{[4
]}

Stivala, F. ^{[4
]}

Milella, M. ^{[5
]}

Tafuri, A. ^{[6
]}

Lunghi, P. ^{[7
]}

Bonati, A. ^{[7
,8
]}

Martelli, A. M. ^{[9
,10
]}

机构：

[1] E Carolina Univ, Dept Microbiol & Immunol, Brody Sch Med, Greenville, NC 27858 USA

[2] ImClone Syst, New York, NY USA

[3] Univ Gottingen, Div Hematol & Oncol, Dept Med, Gottingen, Germany

[4] Univ Catania, Dept Biomed Sci, Catania, Italy

[5] Regina Elena Canc Ctr, Rome, Italy

[6] Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, Rome, Italy

[7] Univ Parma, Dept Clin Sci, I-43100 Parma, Italy

[8] Univ Hosp Parma, Unit Hematol & Bone Marrow Transplantat, Parma, Italy

[9] Univ Bologna, Dept Human Anat Sci, Bologna, Italy

[10] IGM CNR, IOR, Bologna, Italy

来源：

LEUKEMIA | 2008年 / 22卷 / 04期

关键词：

MEK; PI3K; Akt; signal transduction; inhibitors; chemotherapeutic drugs;

D O I：

10.1038/leu.2008.27

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are frequently activated in leukemia and other hematopoietic disorders by upstream mutations in cytokine receptors, aberrant chromosomal translocations as well as other genetic mechanisms. The Jak2 kinase is frequently mutated in many myeloproliferative disorders. Effective targeting of these pathways may result in suppression of cell growth and death of leukemic cells. Furthermore it may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth. In this review, we summarize how suppression of these pathways may inhibit key survival networks important in leukemogenesis and leukemia therapy as well as the treatment of other hematopoietic disorders. Targeting of these and additional cascades may also improve the therapy of chronic myelogenous leukemia, which are resistant to BCR-ABL inhibitors. Furthermore, we discuss how targeting of the leukemia microenvironment and the leukemia stem cell are emerging fields and challenges in targeted therapies.

引用

页码：708 / 722

页数：15

共 174 条

[1] Essential thrombocythemia in young individuals:: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients [J].

Alvarez-Larran, A. ;

Cervantes, F. ;

Bellosillo, B. ;

Giralt, M. ;

Julia, A. ;

Hernandez-Boluda, J. C. ;

Bosch, A. ;

Hernandez-Nieto, L. ;

Clapes, V. ;

Burgaleta, C. ;

Salvador, C. ;

Arellano-Rodrigo, E. ;

Colomer, D. ;

Besses, C. .

LEUKEMIA, 2007, 21 (06) :1218-1223

[2] Gemtuzumab ozogamicin (Mylotarg®) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia:: final results of AML-15B, a phase 2 study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell'Adulto Leukemia Groups [J].

Amadori, S ;

Suciu, S ;

Stasi, R ;

Willemze, R ;

Mandelli, F ;

Selleslag, D ;

Denzlinger, C ;

Muus, P ;

Stauder, R ;

Berneman, Z ;

Pruijt, J ;

Nobile, F ;

Cassibba, V ;

Marie, JP ;

Beeldens, F ;

Baila, L ;

Vignetti, M ;

de Witte, T .

LEUKEMIA, 2005, 19 (10) :1768-1773

[3] Clinical implications of the JAK2 V617F mutation in essential thrombocythemia [J].

Antonioli, E ;

Guglielmelli, P ;

Pancrazzi, A ;

Bogani, C ;

Verrucci, M ;

Ponziani, V ;

Longo, G ;

Bosi, A ;

Vannucchi, AM .

LEUKEMIA, 2005, 19 (10) :1847-1849

[4] Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival [J].

Astier, AL ;

Xu, RH ;

Svoboda, M ;

Hinds, E ;

Munoz, O ;

de Beaumont, R ;

Crean, CD ;

Gabig, T ;

Freedman, AS .

BLOOD, 2003, 101 (03) :1118-1127

[5] Implications of NRAS mutations in AML:: a study of 2502 patients [J].

Bacher, Ulrike ;

Haferlach, Torsten ;

Schoch, Claudia ;

Kern, Wolfgang ;

Schnittger, Susanne .

BLOOD, 2006, 107 (10) :3847-3853

[6] Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines [J].

Barnes, D. J. ;

De, S. ;

van Hensbergen, P. ;

Moravcsik, E. ;

Melo, J. V. .

LEUKEMIA, 2007, 21 (03) :421-426

[7]

Barnes G, 2005, Int J Surg, V3, P206, DOI 10.1016/j.ijsu.2005.04.001

[8] A higher JAK2 V617F-mutated clone is observed in platelets than in granulocytes from essential thrombocythemia patients, but not in patients with polycythemia vera and primary myelofibrosis [J].

Bellosillo, B. ;

Martinez-Aviles, L. ;

Gimeno, E. ;

Florensa, L. ;

Longaron, R. ;

Navarro, G. ;

Salar, A. ;

Espinet, B. ;

Sole, F. ;

Serrano, S. ;

Besses, C. .

LEUKEMIA, 2007, 21 (06) :1331-1332

[9] JAK2 V617F mutation, PRV-1 overexpression and endogenous erythroid colony formation show different coexpression patterns among Ph-negative chronic myeloproliferative disorders [J].

Bellosillo, B ;

Besses, C ;

Florensa, L ;

Sole, F ;

Serrano, S .

LEUKEMIA, 2006, 20 (04) :736-737

[10] Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells [J].

Bertrand, F. E. ;

Steelman, L. S. ;

Chappell, W. H. ;

Abrams, S. L. ;

Shelton, J. G. ;

White, E. R. ;

Ludwig, D. L. ;

McCubrey, J. A. .

LEUKEMIA, 2006, 20 (07) :1254-1260

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