PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.

Margarita Sánchez‐Beato ,Helena Pisonero,Carmen Blanco‐Aparicio ,Manuela Mollejo,Joaquı́n Pastor ,Juan F. Garcı́a ,Miguel Á. Piris ,Javier Menárguez,James R. Bischoff,Carmen Almaráz ,Francisco X. Real,Lina Odqvist,Soraya Curiel del Olmo,Esperanza Martín-Sánchez,Fernando González-Palacios,Rebeca Madureira,Socorro María Rodríguez‐Pinilla ,Giovanna Roncador,Esther González Cantalapiedra,Beatriz Domínguez-González,José Luis Rodríguez‐Peralto ,Pablo L. Ortiz‐Romero ,Ana Collazo ,Francisco Javier Alves

doi:10.1371/journal.pone.0112148

Abstract

Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.

Highlights

Peripheral T cell lymphomas (PTCL) are a very aggressive and heterogeneous group of hematological malignancies [1,2]
PIM kinases as potential therapeutic targets in PTCL First, using microarrays, PIM1 and especially PIM2 genes, but not PIM3, were found to be significantly overexpressed (FDR, 0.05) in tumoral samples from 38 PTCL patients compared with 6 reactive lymph nodes (Figure 1A)
PIM1 and PIM2 expression was significantly correlated with Jak/STAT, NF-kB and IL-2 pathways in our PTCL patient series (Figure 1B), indicating a strong relationship between these pathways and the expression of PIM kinases in PTCL

Summary

Introduction

Peripheral T cell lymphomas (PTCL) are a very aggressive and heterogeneous group of hematological malignancies [1,2]. Several factors are responsible for our limited knowledge, such as the low incidence of PTCL, the heterogeneity of its subtypes and the few representative models (cell lines or mouse models) available. Within the ALCL group, there are two subgroups, depending on the presence or absence of the chromosomal translocation t(2; 5) (p23; q35), which involves the ALK and NPM1 genes and leads to the overexpression of the fusion protein NPM-ALK [3]. This is considered to be the main oncogenic force in ALK+ ALCL, because it activates the Jak/ STAT pathway [5,6]. The ALK+ ALCL is the only PTCL subgroup with a relatively good prognosis [7], around

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