Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation.

Inflammatory and oncogenic signaling converge in disease evolution of BCR-ABL-negative myeloproliferative neoplasms, clonal hematopoietic stem cell disorders characterized by gain-of-function mutation in JAK2 kinase (JAK2V617F), with highest prevalence in patients with polycythemia vera (PV). Despite the high risk, DNA-damaging inflammatory microenvironment, PV progenitors tend to preserve their genomic stability over decades until their progression to post-PV myelofibrosis/acute myeloid leukemia. Using induced pluripotent stem cells-derived CD34+ progenitor-enriched cultures from JAK2V617F+ PV patient and from JAK2 wild-type healthy control, CRISPR-modified HEL cells and patients' bone marrow sections from different disease stages, we demonstrate that JAK2V617F induces an intrinsic IFNγ- and NF-κB-associated inflammatory program, while suppressing inflammation-evoked DNA damage both in vitro and in vivo. We show that cells with JAK2V617F tightly regulate levels of inflammatory cytokines-induced reactive oxygen species, do not fully activate the ATM/p53/p21waf1 checkpoint and p38/JNK MAPK stress pathway signaling when exposed to inflammatory cytokines, suppress DNA single-strand break repair genes' expression yet overexpress the dual-specificity phosphatase (DUSP) 1. RNAi-mediated knock-down and pharmacological inhibition of DUSP1, involved in p38/JNK deactivation, in HEL cells reveals growth addiction to DUSP1, consistent with enhanced DNA damage response and apoptosis in DUSP1-inhibited parental JAK2V617F+ cells, but not in CRISPR-modified JAK2 wild-type cells. Our results indicate that the JAK2V617F+ PV progenitors utilize DUSP1 activity as a protection mechanism against DNA damage accumulation, promoting their proliferation and survival in the inflammatory microenvironment, identifying DUSP1 as a potential therapeutic target in PV.

Diffuse large B-cell lymphoma: the history, current view and new perspectives.

The basic principles of lymphoma classification(s) in general have been widely evolving in a course of decades of years wiht the use of contemporary resources and recent cutting edges in hematooncology on a clinical, morphological and molecular level bring new possibilities not only in improvements of diagnostic and prognostic algorithms and also bear new opportunities in so called targeted and tailored strategies of lymphoma therapy. The pathogenesis and biologic behavior of lymphoproliferations and even lymphomas should be studied in a context of lymphocytic and (neoplastic) lymphoid stage and chronologic development. In a current more complex insight into lymphoproliferations we would like to describe huge heterogeneity of diffuse large B-cell lymphoma in relationship to mandatory WHO classification since 2008 and the next development of knowledge in this field with potential new influence on an advancement of both classification and therapy.

[The importance of cardiac bio-marker assay for the stratification and monitoring of AL amyloidosis patients -  single center experience]. / Význam stanovení kardiálních bio-markeru ve stratifikaci a sledování nemocných s AL amyloidózou -  zkusenosti jednoho centra.

INTRODUCTION: Cardiac involvement is a dominant prognostic factor in AL amyloidosis patients. A detailed assessment of the presence and degree of cardiac involvement utilizes an array of noninvasive investigation methods, particularly echocardiography and MRI; laboratory parameters include troponins and natriuretic peptides. Cardiac involvement detection aside, cardiac bio-markers are used as a relatively strong stratification and prognostic factor. OBJECTIVE: The presentation of cardiac bio-markers assay applications in AL amyloidosis patients at an individual treatment center. PATIENTS AND METHODS: The monitored patient set consisted of 22 patients with histologically confirmed AL amyloidosis, of whom 18 met the criteria for cardiac involvement. Levels of cardiac bio-markers troponin T (TnT) and Nterminal probrain natriuretic peptide (NT ProBNP) were determined in all patients. Risk stratification of the patients utilized the Mayo staging system which is based on both bio-markers assays; Log Rank Test was applied to survival evaluation. RESULTS: Median survival of patients with cardiac involvement stigmata was 10 months vs 60 months survival of patients without signs of cardiac involvement (p = 0.133). Of the 4 patients without cardiac involvement, 1 has shown positive levels of TnT and 2 positive levels of NT ProBNP. All cardiac involvement patients exhibited abnormal levels of NT ProBNP (median 4,752 ng/ l; 415.7- 35,000) as well as positive levels of TnT (median 0.0815 µg/ l; 0.02- 0.986). The application of the Mayo stratification system to the set had determined 2 patients at stage I, 5 patients at stage II and 15 patients at stage III. The median survival of the Mayo I + II group vs the Mayo III group was 60 vs 6 months (p = 0.015), revealing extremely limited survival of stage III patients. Assessment of TnT and NT ProBNP levels relative to treatment response shows that the degree of decrease in both markers depends on maximum treatment response -  respectively the attainment of a complete hematological remission. CONCLUSION: The results, although obtained from a limited set of patients, confirm a definitive benefit of the application of cardiac bio-markers assay in the diagnostic and therapeutic algorithm of AL amyloidosis patients. The Mayo stratification system utilizing the cardiac indicator values represents a robust tool for risk stratification of AL amyloidosis patients.

Determining the extent and stage of disease in patients with newly diagnosed non-Hodgkin's lymphoma using 18F-FDG-PET/CT.

Positron emission tomography (PET) using 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (18F-FDG) combined with computed tomography (CT) represents a three-dimensional imaging method suitable for staging in patients with non-Hodgkin's lymphomas (NHLs). The aim of our prospective multicenter study was to assess the value of initial PET/CT as compared with CT and PET alone for determining the stage and extent of the disease. A total of 122 patients with newly diagnosed NHL were examined using PET/CT. Four patients with resected lymphoma lesion and negative PET/CT were therefore excluded from the study. Of the remaining 118 cases, a total of 117 (99%) were described as 18F-FDG-avid. When compared with PET/CT, CT and PET showed very good sensitivity of lymph node imaging (97% and 100%, respectively); the specificity, however, was significantly lower (66.7% and 94.4%, respectively; p=0.0001). When detecting organ lesions, the sensitivity of CT and PET was lower than that of PET/CT (92.5% and 96.3%, respectively; p=0.0001); specificity was significantly decreased in CT and a little lower in PET (59.5% and 91.9%; p=0.0001). When compared with CT alone, PET/CT changed staging of the disease in 11 patients (9%) and was able to detect a total of 82 discrepancies in 67 of the 117 patients (57%). In conclusion, PET/CT is a new standard in imaging the involvement of lymph nodes and extranodal organs in NHL patients regardless of their histopathological types. Both sensitivity and specificity of the examination are higher than those of CT as well as PET alone.