Pathway activation in large B-cell non-Hodgkin lymphoma cell lines by doxorubicin reveals prognostic markers of in vivo response Journal Article


Authors: Houldsworth, J.; Petlakh, M.; Olshen, A. B.; Chaganti, R. S. K.
Article Title: Pathway activation in large B-cell non-Hodgkin lymphoma cell lines by doxorubicin reveals prognostic markers of in vivo response
Abstract: The principal curative agent in the front-line treatment of patients with diffuse large B-cell lymphoma (DLBCL) is the anthracycline, doxorubicin. To define pathways that may have a functional role in the response of DLBCL in vivo to doxorubicin-based therapies, seven DLBCL cell lines were treated with doxorubicin and the cellular response evaluated. Expression profiling of responses revealed changes in levels of genes consistent with discrete pathway activation that were confirmed functionally. The two most sensitive cell lines (Ly3 and Ly10) displayed activation of the TP53 pathway but not in the remaining five (Ly1, Ly2, Ly4, Ly7 and Ly8), where TP53 mutations were identified. In this latter group, a G2/M delay was invoked. NF-κB pathway activation was evident in Ly1 which with Ly4 displayed the most chemoresistant response. Treatment of Ly1 after doxorubicin with the proteasomic inhibitor, bortezomib, additively increased the cytotoxic effect of doxorubicin. Chemoresistance of Ly4 was associated with loss of chromosome 2 (0-9 Mbp) that in vivo was highly correlated with adverse outcome. Thus, the response of DLBCL in vivo and in vitro is defined by several distinct molecular and genetic pathways which is, perhaps, not surprising given the heterogeneous clinical, morphologic and genetic nature of DLBCL.
Keywords: signal transduction; controlled study; gene mutation; human cell; doxorubicin; drug potentiation; molecular genetics; bortezomib; gene expression profiling; immunoglobulin enhancer binding protein; in vitro study; protein p53; cell specificity; cancer resistance; b cell lymphoma; nonhodgkin lymphoma; drug response; lymphoma; cell cycle arrest; cell cycle g2 phase; cell cycle m phase; large cell lymphoma; drug cytotoxicity; chromosome loss; chromosome 2; prognostication; lymphoma cell line; transcription factor changes
Journal Title: Leukemia and Lymphoma
Volume: 49
Issue: 11
ISSN: 1042-8194
Publisher: Taylor & Francis Group  
Date Published: 2008-01-01
Start Page: 2163
End Page: 2172
Language: English
DOI: 10.1080/10428190802381220
PROVIDER: scopus
PUBMED: 19021061
DOI/URL:
Notes: --- - "Cited By (since 1996): 2" - "Export Date: 17 November 2011" - "CODEN: LELYE" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Adam B Olshen
    107 Olshen
  2. Raju S K Chaganti
    260 Chaganti