PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma

被引：82

作者：

Gomez-Abad, Cristina ^{[1
]}

Pisonero, Helena ^{[1
,2
]}

Blanco-Aparicio, Carmen ^{[3
]}

Roncador, Giovanna ^{[4
]}

Gonzalez-Menchen, Alberto ^{[5
]}

Martinez-Climent, Jose A. ^{[6
]}

Mata, Eva ^{[1
]}

Elena Rodriguez, Maria ^{[1
]}

Munoz-Gonzalez, Guillermo ^{[1
]}

Sanchez-Beato, Margarita ^{[1
]}

Leal, Juan F. ^{[3
]}

Bischoff, James R. ^{[3
]}

Piris, Miguel A. ^{[1
,2
]}

机构：

[1] Spanish Natl Canc Ctr CNIO, Lymphoma Grp, Mol Pathol Programme, E-28049 Madrid, Spain

[2] Hosp Univ Marques Valdecilla, Inst Formac Invest Marques de Valdecilla, Santander, Spain

[3] CNIO, Expt Therapeut Programme, Madrid, Spain

[4] CNIO, Monoclonal Antibodies Unit, Biotechnol Programme, Madrid, Spain

[5] Hosp Reina Sofia, Cordoba, Spain

[6] Fdn Appl Med Res, Oncol Div, Ctr Invest Med Aplicada, Navarra, Spain

来源：

BLOOD | 2011年 / 118卷 / 20期

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; KINASE INHIBITORS; CYCLE PROGRESSION; TRANSGENIC MICE; TUMOR-GROWTH; C-MYC; PROTEIN; PHOSPHORYLATES; EXPRESSION; SURVIVAL;

D O I：

10.1182/blood-2011-03-344374

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

PIM serine/threonine kinases are over-expressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa-associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification. (Blood. 2011;118(20):5517-5527)

引用

页码：5517 / 5527

页数：11