Expression profiles of adult T-cell leukemia–lymphoma and associations with clinical responses to zidovudine and interferon α

Abstract

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 α (IFNα). 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–IFNα 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–IFNα 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–IFNα therapy may provide novel insights into the mechanisms of action in ATLL.

NR4A1-mediated apoptosis suppresses lymphomagenesis and is associated with a favorable cancer-specific survival in patients with aggressive B-cell lymphomas

“…We observed reduced expression of NR4A1 and NR4A3 at mRNA and protein levels in FLII, B-CLL, DLBCL, FLIII, and PMBCL. NR4A1 and NR4A3 mRNA expression was also reduced in publicly available mRNA data sets of global gene expression profiling experiments derived from different B-cell lymphomas [25][26][27][28][29][30][31] in FL and DLBCL, pointing to a tumor suppressive function of both NR4As in certain lymphoma subtypes.…”

IRF7: activation, regulation, modification and function

“…203 (ii) IRF7 is over-expressed in EBV-positive central nervous system lymphomas, 204 as well as in EBV-negative acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, and adult T-cell leukemia/lymphoma. 205,206 (iii) IRF7 induces expression of the EBV principal oncoprotein LMP1 so that they form a regulatory circuit that may potentiate oncogenic effects of both factors. 120 (iv) Moreover, IRF7-expressing NIH 3T3 cells induce tumor formation in nude mice.…”

Gene expression signatures of adult T-cell leukemia: is treatment response prediction on the horizon?

“…This approach was followed in a study reported by Alizadeh and colleagues in this issue of Leukemia and Lymphoma [8]. The authors performed gene expression profiling in a series of patients with adult T-cell leukemia at the time of diagnosis and 24 h after treatment initiation with a combination of zidovudine (AZT) and interferon a (IFNa), in order to identify molecular features of the tumor cells in responding versus non-responding patients.…”

“…While some promising results have been reported in ATLL using a combination therapy of AZT and IFNa [13][14][15], these studies do not offer detailed insights into the underlying molecular mechanisms of response to therapy. Alizadeh's study [8] that reports molecular profiling results of ATLL cells investigated before and after combination therapy with AZT and IFNa sheds some light on this issue. Although the number of patients that were included in the study was quite limited, the authors were able to identify specific gene expression signatures that are associated with the responsiveness of the tumor cells to this therapy.…”