Page 122 - Haematologica-April 2018

Correspondence:
anthony.wright@ki.se
Received: October 10, 2017. Accepted: February 9, 2018. Pre-published: February 15, 2018.
doi:10.3324/haematol.2017.182048
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/4/666
©2018 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
Ferrata Storti Foundation
Non-Hodgkin Lymphoma
Mixed-species RNAseq analysis of human lymphoma cells adhering to mouse stromal cells identifies a core gene set that is also differentially expressed in the lymph node microenvironment of mantle cell lymphoma and chronic lymphocytic leukemia patients
Gustav Arvidsson,1 Johan Henriksson,2 Birgitta Sander3 and Anthony P. Wright4
1Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet; 2Department of Biosciences and Nutrition, Karolinska Institutet; 3Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital and 4Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet Stockholm, Sweden
ABSTRACT
Asubset of hematologic cancer patients is refractory to treatment or suffers relapse, due in part to minimal residual disease, whereby some cancer cells survive treatment. Cell-adhesion-mediated drug resistance is an important mechanism, whereby cancer cells receive sur- vival signals via interaction with e.g. stromal cells. No genome-wide studies of in vitro systems have yet been performed to compare gene expression in different cell subsets within a co-culture and cells grown separately. Using RNA sequencing and species-specific read mapping, we compared transcript levels in human Jeko-1 mantle cell lymphoma cells stably adhered to mouse MS-5 stromal cells or in suspension within a co-culture or cultured separately as well as in stromal cells in co-culture or in separate culture. From 1050 differentially expressed transcripts in adherent mantle cell lymphoma cells, we identified 24 functional cate- gories that together represent four main functional themes, anti-apopto- sis, B-cell signaling, cell adhesion/migration and early mitosis. A compar- ison with previous mantle cell lymphoma and chronic lymphocytic leukemia studies, of gene expression differences between lymph node and blood, identified 116 genes that are differentially expressed in all three studies. From these genes, we suggest a core set of genes (CCL3, CCL4, DUSP4, ETV5, ICAM1, IL15RA, IL21R, IL4I1, MFSD2A, NFKB1, NFKBIE, SEMA7A, TMEM2) characteristic of cells undergoing cell-adhe- sion-mediated microenvironment signaling in mantle cell lymphoma/chronic lymphocytic leukemia. The model system devel- oped and characterized here together with the core gene set will be use- ful for future studies of pathways that mediate increased cancer cell sur- vival and drug resistance mechanisms.
Introduction
Novel therapy regimes have improved the prognosis for many types of lym- phoma and leukemia.1 However, unsolved problems remain for many patients who are refractory to treatment or experience disease relapse. For example, mantle cell lymphoma (MCL) is an aggressive and generally incurable B-cell neoplasm, com- prising about 8% of non-Hodgkin lymphomas (NHL).2 MCL is characterized by a high relapse rate and frequent resistance to therapy, which together with high median age at diagnosis makes MCL difficult to cure. While median overall survival time has doubled in recent years,3 the prognosis for MCL patients is poor with fewer than 15% long-term survivors.4
Signaling pathway defects intrinsic to MCL cells, due to genetic aberrations, pro- vide only a partial explanation for its aggressiveness and frequent relapse. These include the molecular hallmark translocation t(11;14)(q13;q32) CCND1/IGH,
Haematologica 2018 Volume 103(4):666-678
666
haematologica | 2018; 103(4)
ARTICLE