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  • br Results and discussion In this study the


    Results and discussion In this study, the np9 and gag mRNA expression was established for 25 patients with CLL (Fig. 1). We found that the transcriptional activity of HERV-K np9 gene in CLL patients was higher than in PBMCs from healthy donors. The results revealed that 18 out of 25 CLL patients (70% of CLL patients) express np9 transcripts five-fold higher than in normal PBMCs (Fig. 1A). On the other hand when we analyzed gag gene expression we noted that just 33% of CLL patients expressed elevated gag levels (two-fold) compared to healthy people (Fig. 1B). Both in np9 and gag analysis, a wide variability of expression among patients was observed, with no significant difference between mutated and unmutated subgroups (p=0.65 and 0.09 respectively) (see Fig. 1). A previous study regarding HERV-K gag transcriptional activity [2] reported five to eight-fold higher gene expression in 3 B-CLL patients analyzed. However, our study on a large number of B-CLL patients showed that only 2 out of 25 patients exhibited elevated gag expression (5-fold greater than healthy donors) (see Fig. 1B). The overexpression of HERV-K Np9 protein has been observed in a variety of leukemia cell lines and primary cultures of leukemia order WP 1130 [3]. It is known that the interaction of Np9 protein abrogates the function of the promyelocytic leukemia zinc finger (PLZF) as a transcriptional repressor of the c-myc proto-oncogene promoter, resulting in the overproduction of this transcription factor and the induction of cell proliferation [9]. Studies of Palacios et al. [10] in CLL report that the proliferative behavior of a small CLL B-cells subpopulation could be related to expression of c-myc oncogene. Unfortunately our studies on c-myc gene expression levels in CLL patients with high and low np9 mRNA expressions showed no significant differences (p=0.19) in the expression of c-myc between these groups, nor with normal PBMCs (Fig. 2). The differences in these results could be explained by the distinct CLL subpopulations analyzed in each work. Other plausible explanation is that np9 mRNA might not be translated or alternatively, that over expression of c-myc through a putative Np9 PLZF pathway may be transient [9]. To our knowledge, this is the first study of HERV-K np9 mRNA expression in B cell-CLL showing that this molecule is overexpressed in the peripheral blood of CLL patients compared with healthy donors. More studies are needed to evaluate the potential impact of np9 expression on CLL and its role in the regulation of signaling pathways involved in carcinogenesis.
    Conflict of interests
    Authors׳ contributions
    Acknowledgments This work was supported by Fondo Clemente Estable (Grant FCE_6569) from Agencia Nacional de Investigación e Innovación (ANII) and PEDECIBA, Uruguay.
    Case report A 55-year old woman with PV diagnosed in the precursor stage of ET 12 years ago was referred due to intolerance to hydroxyurea (HU) (fever and exanthema) and pegylated interferon-alpha2b (PEG-Intron) (exanthema). Since 2009 the patient had suffered two episodes of transitory cerebral ischemia (TCI). Accordingly, permanent treatment with clopidogrel had been instituted. Several CT-scans were normal. At the time of referral, the patient received treatment with anagrelide and clopidogrel. On admission, the patient׳s hemoglobin concentration was 11.9g/dL, the leukocyte count was 21.9×109/L and the platelet count was elevated at 526×109/L. CRP and plasma lactate dehydrogenase (LDH) levels were normal. A bone marrow biopsy was compatible with a diagnosis of PV with grade 1 reticulin fibrosis. A peripheral blood-smear showed no leucoerythroblastosis. The patient still needed phlebotomies to keep the hematocrit below 0.42, a total of four being performed within the last six months prior to referral. An abdominal ultrasound revealed a spleen length of 20cm giving rise to intermittent spleen pain and abdominal discomfort. Because of hypermetabolic symptoms, pronounced abdominal discomfort, and intolerance of PEG-Intron and HU, treatment with Rux was initiated at a dose of 20mg twice daily and anagrelide was discontinued. Within the first 3 days of Rux therapy, the patient experienced remarkable clinical improvement with resolution of severe fatigue, night sweats, abdominal pain and pruritus, which had negatively influenced the patient׳s quality of life during the past 2–3 years. Four days after starting Rux, the patient acutely experienced TCI-like symptoms with transient decrease of strength in the left arm and abnormal sensations in the left half of the tongue and neck. The symptoms were very similar to those which the patient had experienced during previous attacks of TCIs. The blood values disclosed a slight decrease in the leukocyte count (17.6×109/L) but an increase in the platelet count (573×109/L). A CT-scan was normal. Because the platelets were elevated, Rux therapy was combined with PEG-IFN-alpha2a (Pegasys) at a low dose of 45µg every second week. After 1 month a complete hematologic remission (CHR) was achieved (Fig. 1) and after 2.5 months an abdominal ultrasound revealed a reduction in spleen length from 20cm to 13.8cm. After 6 months the spleen was no longer palpable.