Gene expression and angiotropism in primary CNS lymphoma.
Primary CNS lymphoma is an aggressive form of non-Hodgkin lymphoma whose growth is restricted to the central nervous system. We used cDNA microarray analysis to compare the gene expression signature of primary CNS lymphomas with nodal large B-cell lymphomas. Here, we show that while individual cases of primary CNS lymphomas may be classified as germinal center B-cell, activated B-cell, or type 3 large B-cell lymphoma, brain lymphomas are distinguished from nodal large B-cell lymphomas by high expression of regulators of the unfolded protein response (UPR) signaling pathway, by the oncogenes c-Myc and Pim-1, and by distinct regulators of apoptosis. We demonstrate that interleukin-4 (IL-4) is expressed by tumor vasculature as well as by tumor cells in CNS lymphomas. We also identify high expression in CNS lymphomas of several IL-4-induced genes, including X-box binding protein 1 (XBP-1), a regulator of the UPR. In addition, we demonstrate expression of the activated form of STAT6, a mediator of IL-4 signaling, by tumor cells and tumor endothelia in CNS lymphomas. High expression of activated STAT6 in tumors was associated with short survival in an independent set of patients with primary CNS lymphoma who were treated with high-dose intravenous methotrexate therapy.
Rubenstein
James L
JL
University of California, San Francisco, Division of Hematology/Oncology M1282 Box 1270, 94143, USA. jamesr@medicine.ucsf.edu
Fridlyand
Jane
J
Shen
Arthur
A
Aldape
Ken
K
Ginzinger
David
D
Batchelor
Tracy
T
Treseler
Patrick
P
Berger
Mitchel
M
McDermott
Michael
M
Prados
Michael
M
Karch
Jon
J
Okada
Craig
C
Hyun
William
W
Parikh
Seema
S
Haqq
Chris
C
Shuman
Marc
M
D016543:Central Nervous System Neoplasms / Q000098:blood supply* / Q000145:classification / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000145:classification / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000235:genetics / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000145:classification / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D015847:Interleukin-4