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1.
Leukemia ; 28(9): 1872-84, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24569779

ABSTRACT

Transforming growth factor beta (TGF-ß) has an important role in mediating T-cell suppression in B-cell non-Hodgkin lymphoma (NHL). However, the underlying mechanism responsible for TGF-ß-mediated inhibition of effector memory T (Tm) cells is largely unknown. As reported here, we show that exhaustion is a major mechanism by which TGF-ß inhibits Tm cells, and TGF-ß mediated exhaustion is associated with upregulation of CD70. We found that TGF-ß upregulates CD70 expression on effector Tm cells while it preferentially induces Foxp3 expression in naive T cells. CD70 induction by TGF-ß is Smad3-dependent and involves IL-2/Stat5 signaling. CD70+ T cells account for TGF-ß-induced exhaustion of effector Tm cells. Both TGF-ß-induced and preexisting intratumoral CD70+ effector Tm cells from B-cell NHL have an exhausted phenotype and express higher levels of PD-1 and TIM-3 compared with CD70- T cells. Signaling transduction, proliferation and cytokine production are profoundly decreased in these cells, and they are highly susceptible to apoptosis. Clinically, intratumoral CD70-expressing T cells are prevalent in follicular B-cell lymphoma (FL) biopsy specimens, and increased numbers of intratumoral CD70+ T cells correlate with an inferior patient outcome. These findings confirm TGF-ß-mediated effector Tm cell exhaustion as an important mechanism of immune suppression in B-cell NHL.


Subject(s)
CD27 Ligand/physiology , Immunologic Memory , Lymphoma, B-Cell/immunology , T-Lymphocytes/immunology , Transforming Growth Factor beta/pharmacology , Apoptosis , CD27 Ligand/genetics , Gene Expression Regulation, Neoplastic/drug effects , Hepatitis A Virus Cellular Receptor 2 , Humans , Interleukin-2/physiology , Membrane Proteins/analysis , Programmed Cell Death 1 Receptor/analysis , STAT5 Transcription Factor/physiology , Signal Transduction , Tumor Necrosis Factor Receptor Superfamily, Member 7/physiology
2.
Blood Cancer J ; 1(6): e24, 2011 Jun.
Article in English | MEDLINE | ID: mdl-22829168

ABSTRACT

MicroRNAs (miRNAs) are involved in the regulation of many cellular processes including hematopoiesis, with the aberrant expression of differentiation-stage specific miRNA associated with lymphomagenesis. miRNA profiling has been essential for understanding the underlying biology of many hematological malignancies; however the miRNA signature of the diverse tumor clone associated with Waldenstrom's macroglobulinemia (WM), consisting of B lymphocytes, plasmacytes and lymphoplasmacytic cells, has not been characterized. We have investigated the expression of over 13 000 known and candidate miRNAs in both CD19(+) and CD138(+) WM tumor cells, as well as in their malignant and non-malignant counterparts. Although neither CD19(+) nor CD138(+) WM cells were defined by a distinct miRNA profile, the combination of all WM cells revealed a unique miRNA transcriptome characterized by the dysregulation of many miRNAs previously identified as crucial for normal B-cell lineage differentiation. Specifically, miRNA-9(*)/152/182 were underexpressed in WM, whereas the expression of miRNA-21/125b/181a/193b/223/363 were notably increased (analysis of variance; P<0.0001). Future studies focusing on the effects of these dysregulated miRNAs will provide further insight into the mechanisms responsible for the pathogenesis of WM.

3.
Cancer Res ; 60(8): 2225-31, 2000 Apr 15.
Article in English | MEDLINE | ID: mdl-10786688

ABSTRACT

Two microsatellite instability (MSI) phenotypes have been described in colorectal cancer (CRC): MSI-H (instability at >30% of the loci examined) and MSI-L (MSI at 1-30% of the loci examined). The MSI-H phenotype, observed in both hereditary nonpolyposis colon cancer-associated CRC and approximately 15% of sporadic CRC, generally results from mutational or epigenetic inactivation of the DNA mismatch repair (MMR) genes hMSH2 or hMLH1. The genetic basis for the MSI-L phenotype, however, is unknown. Several other proteins, including hMSH3 and hMSH6, also participate in DNA MMR. Inactivating mutations of MSH6 in yeast and human tumor cell lines are associated with an impaired ability to repair single-base mispairs and small insertion-deletion loops but not large insertion-deletion loops. This suggests that hMSH6 mutations are more likely to be associated with a MSI-L phenotype than a MSI-H phenotype in CRC. To explore this possibility, we screened tumors from 41 patients with MSI-L CRC for hMSH6 mutations with conformation-sensitive gel electrophoresis (CSGE) and for hMSH6 protein expression by immunohistochemistry. Alterations found with CSGE were confirmed by DNA sequencing of normal and tumor tissue. One somatic (Asp389Asn) and 15 germ-line changes were found. Of the 15 germ-line changes, 9 were found in an intron (none involving splice junctions), and 6 were found in an exon (Gly39Glu, Leu395Val, and 4 silent alterations). Immunohistochemical staining for hMSH6 performed on 34 of the 41 tumors revealed strong nuclear hMSH6 expression in all of the cases. Overall, our results suggest that hMSH6 mutations do not play a major role in the development of sporadic CRC with a MSI-L phenotype.


Subject(s)
Colorectal Neoplasms/genetics , DNA-Binding Proteins/genetics , Mutation/genetics , Trinucleotide Repeat Expansion/genetics , Adult , Aged , Aged, 80 and over , Cell Nucleus/metabolism , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , DNA Mutational Analysis , DNA-Binding Proteins/metabolism , Exons/genetics , Family Health , Female , Genetic Testing , Germ-Line Mutation/genetics , Humans , Immunohistochemistry , Introns/genetics , Male , Middle Aged , Phenotype , Polymorphism, Genetic/genetics
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