CD74 is a novel transcription regulator.

CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor. Macrophage migration inhibitory factor binding to CD74 induces its intramembrane cleavage and the release of its cytosolic intracellular domain (CD74-ICD), which regulates cell survival. In the present study, we characterized the transcriptional activity of CD74-ICD in chronic lymphocytic B cells. We show that following CD74 activation, CD74-ICD interacts with the transcription factors RUNX (Runt related transcription factor) and NF-κB and binds to proximal and distal regulatory sites enriched for genes involved in apoptosis, immune response, and cell migration. This process leads to regulation of expression of these genes. Our results suggest that identifying targets of CD74 will help in understanding of essential pathways regulating B-cell survival in health and disease.

[THE ROLE OF THE PLANT ARTEMISIA IN SURVIVAL AND INDUCTION OF APOPTOSIS OF B CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)].

BACKGROUND: The cytotoxic effect of plants such as green tea and turmeric (curcumin) on B chronic lymphocytic leukemia (CLL) cells has been established. The plant Artemisia has been used in China for anti-cancer and anti-malaria applications. In Israel, Artemisia absinthium ("the Chiba") is used to release abdominal pain. In attempts to evaluate the cytotoxic effect of this plant in CLL cells, we prepared a decoction of Artemisia leaves and after filtration used it as an inducer of apoptosis of B CLL cells. METHODS: CLL cells were collected from 7 patients in different stages of the disease. Apoptosis was measured using an annexin based flow cytometry assay. RESULTS: First a viability test showed that 100µl/106 cells was the most effective dilution for killing up to 70% cells after 48 hours of incubation. In these conditions Artemisia induced approximately 75% apoptosis in comparison to 32% in the cultures without Artemisia. CONCLUSIONS: We concluded that decoction of Artemisia absinthium is a potent inducer of in vitro apoptosis of CLL cells. Our results provide a laboratory basis for further clinical application.

Circulating Regulatory B-Lymphocytes in Patients with Acute Myocardial Infarction: A Pilot Study.

Background: Inflammation plays on important role in plaque instability and acute coronary syndromes. The anti-inflammatory effects of B-regulatory lymphocytes (B-regs) in atherosclerosis was tested mainly in animal models with inconclusive results. Herein, we studied for the first time, levels of circulating B-regs in patients with acute myocardial infarction (MI). Methods: We examined circulating levels of B-regs by flow cytometry in 29 patients with recent ST-segment elevation MI and 18 patients with stable angina pectoris (SAP) and coronary artery disease. We re-assessed B-reg levels on average 4 months later. Results: The mean level of CD20+ cells was similar in patients with MI and patients with SAP (p = 0.60). The levels of CD24hiCD38hi cells among CD20+ cells were 5.7 ± 4% and 11.6 ± 6% in patients with MI and SAP, respectively, (p < 0.001). The level of CD24hiCD38hi B-regs remained related to acute MI after correcting for age, gender, and risk factors. Circulating levels of CD24hiCD38hi B-regs in patients with MI did not change significantly at follow-up in a small patient groups (p = 0.408). Conclusions: Circulating B-regs are reduced in patients with MI compared to patients with SAP. This finding may shed further light on the inflammatory pathophysiologic factors related to plaque rupture.

Peripheral Blood Cell Mitochondrial Dysfunction in Myelodysplastic Syndrome Can Be Improved by a Combination of Coenzyme Q10 and Carnitine.

Structural mitochondrial abnormalities and genetic aberrations in mitochondrial proteins have been known in Myelodysplastic syndrome (MDS), yet there is currently little data regarding MDS's metabolic properties and energy production cells. In the current study, we used state-of-the-art methods to assess OXPHOS in peripheral blood cells obtained from MDS patients and healthy controls. We then assessed the effect of food supplements-Coenzyme Q10 and carnitine on mitochondrial function and hematological response. We show here for the first time that there is a significant impairment of mitochondrial respiration in peripheral blood cells in low-risk MDS, which can be improved with food supplements. We also show that these supplements may improve the cytopenia and quality of life.

CD84 regulates PD-1/PD-L1 expression and function in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and progressive accumulation of mature B lymphocytes in the peripheral blood, lymphoid tissues, and bone marrow. CLL is characterized by profound immune defects leading to severe infectious complications. T cells are numerically, phenotypically, and functionally highly abnormal in CLL, with only limited ability to exert antitumor immune responses. Exhaustion of T cells has also been suggested to play an important role in antitumor responses. CLL-mediated T cell exhaustion is achieved by the aberrant expression of several inhibitory molecules on CLL cells and their microenvironment, prominently the programmed cell death ligand 1/programmed cell death 1 (PD-L1/PD-1) receptors. Previously, we showed that CD84, a member of the SLAM family of receptors, bridges between CLL cells and their microenvironment. In the current study, we followed CD84 regulation of T cell function. We showed that cell-cell interaction mediated through human and mouse CD84 upregulates PD-L1 expression on CLL cells and in their microenvironment and PD-1 expression on T cells. This resulted in suppression of T cell responses and activity in vitro and in vivo. Thus, our results demonstrate a role for CD84 in the regulation of immune checkpoints by leukemia cells and identify CD84 blockade as a therapeutic strategy to reverse tumor-induced immune suppression.