Expression profiles of adult T-cell leukemia-lymphoma and associations with clinical responses to zidovudine and interferon alpha.
Adult T-cell leukemia-lymphoma (ATLL) is an HTLV-1-associated lymphoproliferative malignancy that is frequently fatal. We compared gene expression profiles (GEPs) of leukemic specimens from nine patients with ATLL at the time of diagnosis and immediately after combination therapy with zidovudine (AZT) and interferon alpha (IFNalpha). GEPs were also related to genetic aberrations determined by comparative genomic hybridization. We identified several genes anomalously over-expressed in the ATLL leukemic cells at the mRNA level, including LYN, CSPG2, and LMO2, and confirmed LMO2 expression in ATLL cells at the protein level. In vivo AZT-IFNalpha therapy evoked a marked induction of interferon-induced genes accompanied by repression of cell-cycle regulated genes, including those encoding ribosomal proteins. Remarkably, patients not responding to AZT-IFNalpha differed most from responding patients in lower expression of these same IFN-responsive genes, as well as components of the antigen processing and presentation apparatus. Demonstration of specific gene expression signatures associated with response to AZT-IFNalpha therapy may provide novel insights into the mechanisms of action in ATLL.
Alizadeh
Ash A
AA
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Bohen
Sean P
SP
Lossos
Chen
C
Martinez-Climent
Jose A
JA
Ramos
Juan Carlos
JC
Cubedo-Gil
Elena
E
Harrington
William J
WJ
Lossos
Izidore S
IS
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D055028:Comparative Genomic Hybridization; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D015215:Zidovudine / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D014408:Biomarkers, Tumor; D016898:Interferon-alpha; D012333:RNA, Messenger; D015215:Zidovudine