Co-occurrence of polycythemia vera (PV) and diffuse large B-cell lymphoma (DLBCL) – a case study

Czerwienica prawdziwa (polycythemia vera; PV) jest zaliczana do przewlekłych chorób mieloproliferacyjnych i cechuje się zwiększeniem liczby erytrocytów oraz często leukocytów i płytek krwi obwodowej, charakteryzuje się też długim przebiegiem klinicznym. Chłoniak rozlany z dużych komórek B (diffuse large B-cell lymphoma; DLBCL) jest najczęściej występującym chłoniakiem u osób dorosłych i zaliczany jest do chłoniaków o dużej agresywności wymagających szybkiego rozpoczęcia leczenia. Przedstawiamy przypadek chorego, u którego w krótkim odstępie czasu rozpoznano czerwienicę prawdziwą i chłoniaka DLBCL o wyjątkowo agresywnym przebiegu i oporności na stosowaną chemioterapię.Polycythemia vera (PV) is a chronic myeloproliferative disorder characterised by an increased level of erythrocytes and, frequently, leukocytes, as well as platelets, with a long course being its characteristic feature. Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma occurring in adults. Being highly aggressive, it requires immediate treatment. We present a patient with exceptionally aggressive and chemotherapy-resistant DLBCL and polycythemia vera, with a short interval recorded between these disorders being diagnosed

Leczenie nilotynibem chorego na przewlekłą białaczkę szpikową po wcześniejszych niepowodzeniach zastosowania imatynibu i dazatynibu

Introduction of tyrosine kinase inhibitors (TKI) in chronic myelogenous leukemia (CML) hassignificantly improved prognosis. Unfortunately, upon the introduction of TKI treatment, cases oftreatment failure and numerous side effects have been raported. In this paper we present a caseof a patient diagnosed with CML whose treatment was initiated prior to introduction of TKI.Initially, the patient received hydroxyurea and interferon. First-line TKI treatment — imatinib— proved to be ineffective. After 6 months of treatment a minimal cytogenetic response (75% ofPhiladelphia+ [Ph+] cells) was achieved. After 12 months of treatment, no cytogenetic response to imatinib (100% Ph+ cells) was observed. 2nd-line treatment with dasatinib was included.Despite the efficacy of the treatment (the desired levels of cytogenetic and molecular remission wereachieved), the treatment was discontinued due to complications. After 6 days of treatment pleuraleffusion has been reported. Which after discontinuation of therapy and conservative treatment.Relapse of effusion was observed after 6 years of therapy. The presence of fluid in the pleuralcavity was accompanied by extensive infiltration with inflammatory cells. As a next time therapynilotinib was started. Symptoms of intolerance, which were observed initially, spontaneously resolved.Complete cytogenetic remission and a higher molecular response (MR4.5) were achieved.The patient remains under observation.Wprowadzenie do terapii przewlekłej białaczki szpikowej (CML) inhibitorów kinazy tyrozynowej (TKI) znacznie poprawiło rokowanie pacjentów z rozpoznaniem tej choroby. Niestety, wraz z wprowadzeniem leczenia TKI odnotowano przypadki niepowodzeń terapii i liczne działania niepożądane. W pracy opisano przypadek chorego z rozpoznaniem CML w fazie przewlekłej, u którego leczenie rozpoczęto przed wprowadzeniem do terapii TKI. Początkowo chory otrzymywał hydroksymocznik i interferon α. Leczenie pierwszej linii za pomocą TKI — imatynibu — okazało się nieskuteczne. Po 6 miesiącach leczenia uzyskano minimalną odpowiedź cytogenetyczną (75% komórek Filadelfia- -dodatnich [Ph+]), po 12 miesiącach stwierdzono brak odpowiedzi cytogenetycznej na imatynib (100% komórek Ph+). Włączono leczenie drugiej linii dazatynibem. Mimo skuteczności stosowanego leczenia (uzyskano pożądane poziomy remisji cytogenetycznej i molekularnej) przerwano je z powodu powikłań. Po 6 dniach stwierdzono u chorego wysięk opłucnowy. Zmiany ustąpiły po odstawieniu leku i leczeniu zachowawczym. Nawrót wysięku stwierdzono po 6 latach terapii. Obecności płynu w jamach opłucnowych towarzyszyły rozległe nacieki z komórek zapalnych. W kolejnym etapie rozpoczęto leczenie nilotynibem. Początkowo obserwowane objawy nietolerancji ustąpiły. W badaniach kontrolnych utrzymują się całkowita remisja cytogenetyczna oraz większa odpowiedź molekularna (MR4,5). Pacjent pozostaje pod kontrolą

Rola i potencjał terapeutyczny sfingolipidowego szlaku sygnalizacyjnego w nowotworach hematologicznych

One of the key obstacles in the progress of cancer treatment is the lack of balance between theuncontrolled proliferation and cell apoptosis. It is now known that sphingolipids are essentialmolecules regulating the processes of growth, differentiation and death of living cells. Dependingon their chemical nature, sphingolipids may have a stimulatory (S1P, sphingosine-1-phosphate)or inhibitory (ceramide) effect on cellular proliferation. A number of different studies have shownthat the generation of ceramide in response to cytotoxic therapy is an important element leadingto cell death. Cancer cells use different methods limiting the production of ceramides that leads totheir removal. The effect of oncogenic S1P results from its stimulating effect on DNA synthesisand chemotactic mobility of the vascular endothelial cells and angiogenesis. The use of monoclonalanti-S1P antibodies is potentially a valuable therapeutic option for inhibiting angiogenesisdetermining the growth of tumors. It was additionally demonstrated that S1P beyond the directand indirect by stimulating the release of vascular endothelial growth factor and basic fibroblastgrowth factor angiogenic action has an effect on tumor growth and its metastatic potential. Amongthe sphingolipids, ceramide was identified first as inducing differentiation and the death of humanHL-60 promyelocytic leukemia cells. Progress in understanding the role of sphingolipids wasregarded until recently as the only structural component of cell membranes allowing the use in thetreatment of complex properties of this group of signaling molecules. Thus, it has become importantto clarify the role of sphingolipids in the regulation of the balance between proliferation signals//survival rate and death of cells in order to develop new therapies for neoplastic diseases of myeloidand lymphoid origin.Brak skutecznych metod pozwalających na osiągnięcie równowagi między niekontrolowaną proliferacją i apoptozą komórek w procesie nowotworowym stanowi jedną z kluczowych barier postępu w leczeniu. Obecnie wiadomo, że istotnymi cząsteczkami regulującymi procesy wzrostu, różnicowania, życia oraz śmierci komórek są sfingolipidy. Zależnie od natury chemicznej sfingolipidy mogą pobudzać (S1P, sfingozyno-1-fosforan) lub hamować (ceramid) proliferację. W wielu różnych badaniach wykazano, że generacja ceramidu w odpowiedzi na terapię cytotoksyczną jest ważnym elementem prowadzącym do śmierci komórki. Komórki nowotworowe stosują różne sposoby ograniczające wytwarzanie ceramidu i prowadzące do jego usuwania. Działanie onkogenne S1P wynika z jego działania stymulującego syntezę DNA i ruchliwość chemotaktyczną komórek śródbłonka naczyniowego, jak również stymulacji rozwoju naczyń krwionośnych. Dlatego zastosowanie przeciwciał monoklonalnych anty-S1P jest potencjalnie wartościową opcją terapeutyczną w hamowaniu rozwoju naczyń krwionośnych warunkujących wzrost guzów nowotworowych. Dodatkowo udowodniono, że S1P poza bezpośrednim oraz pośrednim — przez stymulację uwalniania czynnika wzrostu śródbłonka naczyniowego i podstawowy czynnik wzrostu fibroblastów — działaniem angiogennym, wpływa na wzrost i potencjał przerzutowy nowotworów. Spośród sfingolipidów ceramid wskazano jako pierwszy indukujący różnicowanie i śmierć w komórkach ludzkiej białaczki promielocytowej HL-60. Postęp w zrozumieniu roli sfingolipidów, uważanych do niedawna za jedynie składową strukturalną błon komórkowych, umożliwia wykorzystanie w terapii złożonych właściwości tej grupy cząsteczek sygnalizacyjnych. Istotne więc stało się wyjaśnienie roli sfingolipidów w regulacji równowagi między sygnałami proliferacji/przeżywalności komórek i ich śmierci w celu opracowania nowych terapii

A common variant within the HNF1B gene is associated with overall survival of multiple myeloma patients: results from the IMMEnSE consortium and meta-analysis

Diabetogenic single nucleotide polymorphisms (SNPs) have recently been associated with multiple myeloma (MM) risk but their impact on overall survival (OS) of MM patients has not been analysed yet. In order to investigate the impact of 58 GWAS-identified variants for type 2 diabetes (T2D) on OS of patients with MM, we analysed genotyping data of 936 MM patients collected by the International Multiple Myeloma rESEarch (IMMENSE) consortium and an independent set of 700 MM patients recruited by the University Clinic of Heidelberg. A meta-analysis of the cox regression results of the two sets showed that rs7501939 located in the HNF1B gene negatively impacted OS (HRRec = 1.44, 95% CI = 1.18-1.76, P = 0.0001). The meta-analysis also showed a noteworthy gender-specific association of the SLC30A8(rs13266634) SNP with OS. The presence of each additional copy of the minor allele at rs13266634 was associated with poor OS in men whereas no association was seen in women (HRMen-Add = 1.32, 95% CI 1.13-1.54, P = 0.0003). In conclusion, these data suggest that the HNF1B(rs7501939) SNP confers poor OS in patients with MM and that a SNP in SLC30A8 affect OS in men.This work was supported by grants from the FIBAO foundation (Granada, Spain), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688) and from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]).FIBAO foundation (Granada, Spain), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688) and from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]info:eu-repo/semantics/publishedVersio

A polygenic risk score for multiple myeloma risk prediction

This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis.There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.University of Pisa, DKFZUniversity Hospital of Southern Jutland, DenmarkInstitut National du Cancer (INCA) Franc

Polymorphisms within autophagy-related genes as susceptibility biomarkers for multiple myeloma: a meta-analysis of three large cohorts and functional characterization

Functional data used in this project have been meticulously catalogued and archived in the BBMRI-NL data infrastructure (https://hfgp.bbmri.nl/, accessed on 12 February 2020) using the MOLGENIS open-source platform for scientific data.Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte hemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP corre lated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+ IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4 ) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4 ). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways.This work was supported by the European Union’s Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845), Consejería de Transformación Económica, Industria, Conocimiento y Universidades and FEDER (PY20/01282), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]), and from National Cancer Institute of the National Institutes of Health under award numbers: R01CA186646, U01CA249955 (EEB).This work was also funded d by Portuguese National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

[Excerpt] Multiple myeloma (MM) is the third most common hematological malignancy, after Non-Hodgkin Lymphoma and Leukemia. MM is generally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS) [1], and epidemiological studies have identified older age, male gender, family history, and MGUS as risk factors for developing MM [2]. The somatic mutational landscape of sporadic MM has been increasingly investigated, aiming to identify recurrent genetic events involved in myelomagenesis. Whole exome and whole genome sequencing studies have shown that MM is a genetically heterogeneous disease that evolves through accumulation of both clonal and subclonal driver mutations [3] and identified recurrently somatically mutated genes, including KRAS, NRAS, FAM46C, TP53, DIS3, BRAF, TRAF3, CYLD, RB1 and PRDM1 [3,4,5]. Despite the fact that family-based studies have provided data consistent with an inherited genetic susceptibility to MM compatible with Mendelian transmission [6], the molecular basis of inherited MM predisposition is only partly understood. Genome-Wide Association (GWAS) studies have identified and validated 23 loci significantly associated with an increased risk of developing MM that explain ~16% of heritability [7] and only a subset of familial cases are thought to have a polygenic background [8]. Recent studies have identified rare germline variants predisposing to MM in KDM1A [9], ARID1A and USP45 [10], and the implementation of next-generation sequencing technology will allow the characterization of more such rare variants. [...]French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organizatio

Extracellular DNA as an essential component and therapeutic target of microbial biofilm

The dominant part of human infections is associated with biofilm formations. Biofilm represents structured communities of bacterial or fungal cells enclosed in self-produced polymeric matrixes adherent to supporting surfaces. Microbial DNA and the host cell DNA, after their release at the infection site, show the ability to promote biofilm formation. Between the different constituents of biofilm matrixes, extracellular DNA (eDNA) may be the only component indispensable for the initial attachment and early biofilm formation through an enhanced matrix structural integrity. The effect of DNA on bacterial/fungal attachment is non-specific, as indicated by the stimulatory effect of plasmid, chromosome, or eukaryotic DNA. DNase I impaired bacterial biofilm growth and the targeting eDNA were recently proposed to eliminate and/or prevent different microbial infections associated with biofilm formations