Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo

被引:9
作者
Alsadeq, A. [1 ]
Strube, S. [1 ]
Krause, S. [1 ]
Carlet, M. [2 ]
Jeremias, I. [2 ]
Vokuhl, C. [3 ]
Loges, S. [4 ,5 ]
Aguirre-Ghiso, J. A. [6 ,7 ]
Trauzold, A. [8 ]
Cario, G. [1 ]
Stanulla, M. [9 ]
Schrappe, M. [1 ]
Schewe, D. M. [1 ]
机构
[1] Univ Hosp Schleswig Holstein, ALL BFM Study Grp, Dept Gen Pediat, D-24105 Kiel, Germany
[2] Helmholtz Zentrum Munchen, Dept Gene Vectors, Res Ctr Environm Hlth, Munich, Germany
[3] Univ Kiel, Dept Pediat Pathol, Kiel Pediat Tumor Registry, Kiel, Germany
[4] Univ Hosp Eppendorf, Med Clin 2, Hamburg, Germany
[5] Univ Hosp Eppendorf, Inst Tumor Biol, Hamburg, Germany
[6] Mt Sinai Sch Med, Dept Med, Div Hematol & Oncol, New York, NY USA
[7] Mt Sinai Sch Med, Dept Otolaryngol, New York, NY USA
[8] Univ Kiel, Inst Expt Canc Res, Div Mol Oncol, Kiel, Germany
[9] Hannover Med Sch, Dept Pediat Hematol Oncol, Hannover, Germany
关键词
ACTIVATED PROTEIN-KINASE; GLUCOCORTICOID-INDUCED APOPTOSIS; TUMOR-CELL QUIESCENCE; OF-FUNCTION MUTATIONS; MARROW STROMAL CELLS; BONE-MARROW; INITIATE LEUKEMIA; MULTIPLE-MYELOMA; BIM INDUCTION; LATE RELAPSES;
D O I
10.1038/leu.2015.153
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
P38 alpha/beta has been described as a tumor-suppressor controlling cell cycle checkpoints and senescence in epithelial malignancies. However, P38 alpha/beta also regulates other cellular processes. Here, we describe a role of P38 alpha/beta as a regulator of acute lymphoblastic leukemia (ALL) proliferation and survival in experimental ALL models. We also report first evidence that P38 alpha/beta phosphorylation is associated with the occurrence of relapses in TEL-AML1-positive leukemia. First, in vitro experiments show that P38 alpha/beta signaling is induced in a cyclical manner upon initiation of proliferation and remains activated during log-phase of cell growth. Next, we provide evidence that growth-permissive signals in the bone marrow activate P38 alpha/beta in a novel avian ALL model, in which therapeutic targeting can be tested. We further demonstrate that P38 alpha/beta inhibition by small molecules can suppress leukemic expansion and prolong survival of mice bearing ALL cell lines and primary cells. Knockdown of p38 alpha strongly delays leukemogenesis in mice xenografted with cell lines. Finally, we show that in xenografted TEL-AML1 patients, ex vivo P38 alpha/beta phosphorylation is associated with an inferior long-term relapse-free survival. We propose P38 alpha/beta as a mediator of proliferation and survival in ALL and show first preclinical evidence for P38 alpha/beta inhibition as an adjunct approach to conventional therapies.
引用
收藏
页码:2307 / 2316
页数:10
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