Targeting p53 in chronic lymphocytic leukemia.

Genomic studies have allowed to identify molecular predictors for chronic lymphocytic leukemia (CLL) treatment tailoring.The review covers the p53 biological pathway, its genetic alterations and clinical implications in CLL, and its druggable targets. The potential therapeutic options forThe key approach to improve CLL outcome is treatment tailoring in individual patients. BCR and BCL2 inhibitors have significantly improved CLL survival, howeve

Molecular analysis of different clinical presentations of chronic lymphocytic leukemia reveals novel molecular predictors and molecular heterogenety of different anatomical compartments

Chronic lymphocytic leukemia (CLL) and Small lymphocytic lymphoma (SLL) are different manifestation of the same lymphoproliferative disease. Our study aims at evaluating molecular markers that predispose to chemorefractoriness in CLL and to identify molecular landscape of the different anatomical compartments of SLL. Fludarabine, cyclophosphamide, and rituximab (FCR) is the most effective chemoimmunotherapy regimen for young and fit CLL patients devoid of TP53 disruption. A cohort of 287 patients receiving first-line FCR was analyzed by next generation sequencing (NGS). By univariate analysis, BIRC3 mutations identify a poor prognostic subgroup of patients failing FCR (p<0.001) as cases harboring TP53 mutations (p<0.001). BIRC3 mutations maintained an independent association with an increased risk of progression (p=0.004) in multivariate analysis. By immunoblotting analysis, we showed that the non-canonical NF-KB pathway is active in BIRC3 mutated cell lines and in primary CLL samples. In vitro results indicate that BIRC3 mutated primary CLL cells are less sensitive to fludarabine. BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel drugs. Regarding SLL, we investigated 12 SLL patients, provided with: cell free DNA (CfDNA) from plasma, genomic DNA (gDNA) from LNF biopsies, gDNA from CD19+ cells and from CD3+ cells, by using NGS. By comparing mutations identified, SLL genotyping on the cfDNA does not recapitulate SLL genetics and lacks 65.2% identified in the PB CD19+ cells and in the LNF. By considering the 44 mutations identified in the LNF and in the PB CD19+ cells, 20.4% of mutations were unique to the LNF biopsy, 36.4% were unique to the PB CD19+ cells and only 43.2% were shared. The analysis of the LNF only or of the PB CD19+ cell only may miss mutations with potential clinical relevance, suggesting that both these two compartments should be tested to have a comprehensive view of the SLL genetics relevance

Liquid biopsy in lymphomas: a potential tool for refining diagnosis and disease monitoring

Liquid biopsy consists in a simple blood sampling that allows to analyze cell free DNA (cfDNA), containing specific genomic clues released by the tumor into the bloodstream. In this review, we shall focus on the analysis of cfDNA in lymphoma and, in particular, on its application in the genotyping and monitoring of two common types of B-cell lymphoma, i.e., diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). From a diagnostic standpoint and based upon the current international guidelines, lymphoma diagnosis has so far relied on the analysis of the tissue biopsy. From a molecular viewpoint, though, the tissue biopsy does not reflect the entire molecular heterogeneity of lymphomas. In fact, in an individual patient, lymph nodes at different anatomical sites, as well as different areas of the same lymph node, may show different genetic profiles. Consequently, molecular analysis of genomic DNA extracted from a single lymph node biopsy may not recapitulate the whole mutational landscape of the disease. Liquid biopsy may overcome this hurdle, since cfDNA is released by all tumoral cells and can reveal the entire molecular complexity of lymphomas. From a translational perspective, liquid biopsy may also be used to evaluate clonal evolution, response to therapy and minimal residual disease. Consistently, in DLBCL as well in cHL, the drop of the mutational burden during the treatment course provides complementary information to conventional imaging techniques. The integration of liquid biopsy with imaging techniques may prove useful for a better prediction of patients’ outcome and for a better treatment tailoring

Clonally unrelated Richter syndrome are truly de novo diffuse large B-cell lymphomas with a mutational profile reminiscent of clonally related Richter syndrome

Richter syndrome (RS) is mostly due to the direct transformation of the chronic lymphocytic leukaemia (CLL) clone, as documented by the same immunoglobulin heavy-chain variable region (IGHV) rearrangement in both CLL and RS cells. In rare cases characterized by a better outcome, the RS clone harbours a different IGHV rearrangement compared to the CLL phase. We investigated the CLL phase of clonally unrelated RS to test whether the RS clone was already identifiable prior to clinicopathologic transformation, albeit undetectable by conventional approaches. CLL cells of eight patients with unrelated RS were subjected to an ultra-deep next-generation sequencing (NGS) approach with a sensitivity of 10(-6). In 7/8 cases, the RS rearrangement was not identified in the CLL phase. In one case, the RS clone was identified at a very low frequency in the CLL phase, conceivably due to the concomitance of CLL sampling and RS diagnosis. Targeted resequencing revealed that clonally unrelated RS carries genetic lesions primarily affecting the TP53, MYC, ATM and NOTCH1 genes. Conversely, mutations frequently involved in de novo diffuse large B-cell lymphoma (DLBCL) without a history of CLL were absent. These results suggest that clonally unrelated RS is a truly de novo lymphoma with a mutational profile reminiscent, at least in part, of clonally related RS

THE UKRAINIAN STEPPE AS A REGION OF INTERCULTURAL CONTACTS BETWEEN ATLANTIC AND MEDITERRANEAN ZONES OF EUROPEAN MESOLITHIC

his volume contains the majority of the papers presented during a conference that took place on 16th-21st May, 1997 in Łódź, Poland. The conference was organized by the Institute of Archaeology, University of Łódź and Département d'anthropologie, Université de Montreal (Canada). The conference was funded by the University of Łódź and by IREX (International Research & Exchanges Board), which also supported this publication. The publication was partly founded by the University of Łódź and by the Foundation of Adam Mickiewicz University, too. The major questions of the conference were, 1) what is the current evidence for eastern or southern influences in the development of eastern European Mesolithic and Neolithic populations, and 2) to what extent are current political trends, especially the reassertion or, in some cases, the creation of ethnic and national identities, influencing our interpretations of the prehistoric data. The idea for such a conference came into being through the co-organizers' long-term studies of the development of those prehistoric human populations which inhabited the vast region stretching north and east from the Oder river and Carpathian Mountains to the foothills of the Urals. In a tradition established in modern times by Gordon Childe, virtually all of the transformations of Eastern Europe's Neolithic Age human landscape have been assumed to be responses to prior developments in the Balkan peninsula and Danube basin. We think that a body of new evidence requires a renewed analysis of the distributions of cultural products, peoples, and ideas across Eastern Europe during the Mesolithic through the Early Metal Age within a much wider geographic context than previously has been the case. This includes giving adequate attention to the far-ranging interactions of communities between the Pontic and Baltic area with those located in both the Caucasus and the Aralo-Caspian regions. We hope that this volume will contribute to such a redirection of future analyses