MicroRNA Expression Profiling Identifies Activated B Cell Status in Chronic Lymphocytic Leukemia Cells

Chronic lymphocytic leukemia (CLL) is thought to be a disease of resting lymphocytes. However, recent data suggest that CLL cells may more closely resemble activated B cells. Using microRNA (miRNA) expression profiling of highly-enriched CLL cells from 38 patients and 9 untransformed B cells from normal donors before acute CpG activation and 5 matched B cells after acute CpG activation, we demonstrate an activated B cell status for CLL. Gene set enrichment analysis (GSEA) identified statistically-significant similarities in miRNA expression between activated B cells and CLL cells including upregulation of miR-34a, miR-155, and miR-342-3p and downregulation of miR-103, miR-181a and miR-181b. Additionally, decreased levels of two CLL signature miRNAs miR-29c and miR-223 are associated with ZAP70+ and IgVH unmutated status and with shorter time to first therapy. These data indicate an activated B cell status for CLL cells and suggest that the direction of change of individual miRNAs may predict clinical course in CLL

Identification and characterization of a new member of the gas3/PMP22 gene family in C. elegans

The Gas3/PMP22 protein family is characterized by tetraspan transmembrane proteins. The gas3/PMP22 gene is highly expressed in Schwann cells of the peripheral nervous system, and different alterations of this gene are associated with hereditary demyelinating neuropathies, such as the Charcot-Marie-Tooth type 1A, the Dejerine-Sottas syndrome and the Hereditary Liability to Pressure Palsies (HNPP). Here, we report on the identification of at least one member of the Gas3/PMP22 family in the nematode C. elegans (C01C10.1b). C01C10.1b shares 36% of identical amino acids with the human Gas3/PMP22 and is characterized by four hydrophobic putative transmembrane domains. It lacks the typical N-linked glycosylation consensus in the first extracellular loop. C01C10.1b is transcribed as an operon downstream to the gene C01C10. In, which encodes for a putative tetraspan protein with less conserved homology with the Gas3/PMP22 family. Interestingly, C01C10.1a contains three N-glycosylation sites at the C-terminus. Both genes are expressed in different nematode developmental stages and in the adults. The characterization of one member of the gas3/PMP22 family in C. elegans gives the opportunity to use this model organism to investigate the role of gas3/PMP22 in the regulation of cell proliferation and differentiation and its relation to the hereditary neurodegenerative diseases in humans

MAGE-A tumor antigens target p53 transactivation function through HDACs recruitment and confer resistance to chemotherapeutic agents

The MAGE gene family is characterized by a conserved domain (MAGE Homology Domain). A subset of highly homologous MAGE genes (group A; MAGE-A) belong to the chromosome X-clustered cancertestis antigens. MAGE-A genes are normally expressed in the human germ line and overexpressed in various tumor types; however, their biological function is largely unknown. Here we present evidence indicating that MageA2 protein, belonging to the MAGE-A subfamily, confers wild-type-p53-sensitive resistance to etoposide (ET) by inducing a novel p53 inhibitory loop involving recruitment of histone deacetylase 3 (HDAC3) to MageA2p53 complex, thus strongly down-regulating p53 transactivation function. In fact, enhanced MageA2 protein levels, in addition to ET resistance, correlate with impaired acetylation of both p53 and histones surrounding p53-binding sites. Association between MAGE-A expression levels and resistance to ET treatment is clearly shown in short-term cell lines obtained from melanoma biopsies harboring wild-type-p53, whereas cells naturally, or siRNAmediated expressing low MAGE-A levels, correlate with enhanced p53-dependent sensitivity to ET. In addition, combined trichostatin AET treatment in melanoma cells expressing high MAGE-A levels reestablishes p53 response and reverts the chemoresistance

The proliferative response to CpG-ODN stimulation predicts PFS, TTT and OS in patients with chronic lymphocytic leukemia

We recently reported that leukemic cells from IgVH-unmutated/progressive CLL more frequently proliferate in response to CpG-ODN stimulation than their corresponding counterparts. Here we evaluated the prognostic impact of this proliferative response in 91 CLL patients. The proliferative response was highly predictive of PFS, TTT and OS in the whole series and refined prognosis in patients with M-CLL. BCR stimulation modulated the response to CpG-ODN, suggesting that the proliferative capacity of the leukemic cells is related to antigen-encounter history. These data support the hypothesis that the capacity of the leukemic cells to respond to external stimuli influences disease progression in CLL