Browsing by Subject "LEUKEMIA"

Sort by: Order: Results:

Now showing items 1-11 of 11
  • Gasparini, Vanessa Rebecca; Binatti, Andrea; Coppe, Alessandro; Teramo, Antonella; Vicenzetto, Cristina; Calabretto, Giulia; Barila, Gregorio; Barizza, Annica; Giussani, Edoardo; Facco, Monica; Mustjoki, Satu; Semenzato, Gianpietro; Zambello, Renato; Bortoluzzi, Stefania (2020)
    The molecular pathogenesis of chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is poorly understood. Following the screening of 57 CLPD-NK patients, only five presented STAT3 mutations. WES profiling of 13 cases negative for STAT3/STAT5B mutations uncovered an average of 18 clonal, population rare and deleterious somatic variants per patient. The mutational landscape of CLPD-NK showed that most patients carry a heavy mutational burden, with major and subclonal deleterious mutations co-existing in the leukemic clone. Somatic mutations hit genes wired to cancer proliferation, survival, and migration pathways, in the first place Ras/MAPK, PI3K-AKT, in addition to JAK/STAT (PIK3R1 and PTK2). We confirmed variants with putative driver role of MAP10, MPZL1, RPS6KA1, SETD1B, TAOK2, TMEM127, and TNFRSF1A genes, and of genes linked to viral infections (DDX3X and RSF1) and DNA repair (PAXIP1). A truncating mutation of the epigenetic regulator TET2 and a variant likely abrogating PIK3R1-negative regulatory activity were validated. This study significantly furthered the view of the genes and pathways involved in CLPD-NK, indicated similarities with aggressive diseases of NK cells and detected mutated genes targetable by approved drugs, being a step forward to personalized precision medicine for CLPD-NK patients.
  • Mehtonen, Juha; Polonen, Petri; Häyrynen, Sergei; Dufva, Olli; Lin, Jake; Liuksiala, Thomas; Granberg, Kirsi; Lohi, Olli; Hautamäki, Ville; Nykter, Matti; Heinäniemi, Merja (2019)
    Existing large gene expression data repositories hold enormous potential to elucidate disease mechanisms, characterize changes in cellular pathways, and to stratify patients based on molecular profiles. To achieve this goal, integrative resources and tools are needed that allow comparison of results across datasets and data types. We propose an intuitive approach for data-driven stratifications of molecular profiles and benchmark our methodology using the dimensionality reduction algorithm t-distributed stochastic neighbor embedding (t-SNE) with multi-study and multi-platform data on hematological malignancies. Our approach enables assessing the contribution of biological versus technical variation to sample clustering, direct incorporation of additional datasets to the same low dimensional representation, comparison of molecular disease subtypes identified from separate t-SNE representations, and characterization of the obtained clusters based on pathway databases and additional data. In this manner, we performed an integrative analysis across multi-omics acute myeloid leukemia studies. Our approach indicated new molecular subtypes with differential survival and drug responsiveness among samples lacking fusion genes, including a novel myelodysplastic syndrome-like cluster and a cluster characterized with CEBPA mutations and differential activity of the S-adenosylmethionine-dependent DNA methylation pathway. In summary, integration across multiple studies can help to identify novel molecular disease subtypes and generate insight into disease biology.
  • Kuuluvainen, Emilia; Domenech-Moreno, Eva; Niemela, Elina H.; Makela, Tomi P. (2018)
    In cancer, oncogene activation is partly mediated by acquired superenhancers, which therefore represent potential targets for inhibition. Superenhancers are enriched for BRD4 and Mediator, and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of superenhancer-associated genes in stem cells. Here we show that depletion of Mediator kinase module subunit MED12 or MED13 together with MED13L can be used to reduce expression of cancer-acquired superenhancer genes, such as the MYC gene, in colon cancer cells, with a concomitant decrease in proliferation. Whereas depletion of MED12 or MED13/MED13L caused a disproportional decrease of superenhancer gene expression, this was not seen with depletion of the kinases cyclin-dependent kinase 9 (CDK8) and CDK19. MED12-MED13/MED13L-dependent superenhancer genes were coregulated by beta-catenin, which has previously been shown to associate with MED12. Importantly, beta-catenin depletion caused reduced binding of MED12 at the MYC superenhancer. The effect of MED12 or MED13/MED13L depletion on cancer-acquired superenhancer gene expression was more specific than and partially distinct from that of BRD4 depletion, with the most efficient inhibition seen with combined targeting. These results identify a requirement of MED12 and MED13/MED13L for expression of acquired superenhancer genes in colon cancer, implicating these Mediator subunits as potential therapeutic targets for colon cancer, alone or together with BRD4.
  • Raj, Kavita; Eikema, Diderik-Jan; McLornanl, Donal P.; Olavarria, Eduardo; Bloke, Henric-Jan; Bregante, Stefania; Ciceri, Fabio; Passweg, Jakob; Ljungman, Per; Schaap, Nicolaas; Carlson, Kristina; Zuckerman, Tsila; de Wreede, Liesbeth C.; Volin, Liisa; Koc, Yener; Luis Diez-Martin, Jose; Brossart, Peter; Wolf, Dominik; Blaise, Didier; Di Bartolomeo, Paolo; Vitek, Antonin; Robin, Marie; Yakoub-Agha, Ibrahim; Chalandon, Yves; Kroger, Nicolaus (2019)
    This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57 years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34(+) cell dose was 4.8 x 10(6)/kg (range, 1.7 to 22.9; n = 43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28 days was 82% (range, 70% to 93%), at a median of 21 days (range, 19 to 23). At 2 years the cumulative incidence of primary graft failure was 9% (95% CI 1% to 16%) and secondary graft failure was 13% (95% CI 4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and Ill to IV was 28% (95% CI 16% to 40%) and 9% (95% CI 2% to 17%) at 100 days. The cumulative incidence of chronic GVHD at 1 year was 45% (95% CI 32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (95% CI 10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (95% CI 48% to 74%) and 56% (95% CI 41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (95% CI 45% to 71%) and 43% (95% CI 28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% 95% CI 7% to 31%). The 2-year nonrelapse mortality was 38% (95% CI 24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion. (C) 2018 American Society for Blood and Marrow Transplantation.
  • Ritari, J.; Hyvärinen, K.; Koskela, S.; Itälä-Remes, M.; Niittyvuopio, R.; Nihtinen, A.; Salmenniemi, U.; Putkonen, M.; Volin, L.; Kwan, T.; Pastinen, T.; Partanen, J. (2019)
    Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63-0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.
  • Halkola, Anni S.; Parvinen, Kalle; Kasanen, Henna; Mustjoki, Satu; Aittokallio, Tero (2020)
    Each patient’s cancer has a unique molecular makeup, often comprised of distinct cancer cell subpopulations. Improved understanding of dynamic processes between cancer cell populations is therefore critical for making treatment more effective and personalized. It has been shown that immunotherapy increases the survival of melanoma patients. However, there remain critical open questions, such as timing and duration of immunotherapy and its added benefits when combined with other types of treatments. We introduce a model for the dynamics of active killer T-cells and cancer cell subpopulations. Rather than defining the cancer cell populations based on their genetic makeup alone, we consider also other, non-genetic differences that make the cell populations either sensitive or resistant to a therapy. Using the model, we make predictions of possible outcomes of the various treatment strategies in virtual melanoma patients, providing hypotheses regarding therapeutic efficacy and side-effects. It is shown, for instance, that starting immunotherapy with a denser treatment schedule may enable changing to a sparser schedule later during the treatment. Furthermore, combination of targeted and immunotherapy results in a better treatment effect, compared to mono-immunotherapy, and a stable disease can be reached with a patient-tailored combination. These results offer better understanding of the competition between T-cells and cancer cells, toward personalized immunotherapy regimens.
  • Baliakas, Panagiotis; Tesi, Bianca; Wartiovaara-Kautto, Ulla; Stray-Pedersen, Asbjørg; Friis, Lone Smidstrup; Dybedal, Ingunn; Hovland, Randi; Jahnukainen, Kirsi; Raaschou-Jensen, Klas; Ljungman, Per; Rustad, Cecilie F.; Lautrup, Charlotte K.; Kilpivaara, Outi; Kittang, Astrid Olsnes; Grønbæk, Kirsten; Cammenga, Jörg; Hellstrom-Lindberg, Eva; Andersen, Mette K. (2019)
    Myeloid neoplasms (MNs) with germline predisposition have recently been recognized as novel entities in the latest World Health Organization (WHO) classification for MNs. Individuals with MNs due to germline predisposition exhibit increased risk for the development of MNs, mainly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Setting the diagnosis of MN with germline predisposition is of crucial clinical significance since it may tailor therapy, dictate the selection of donor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), determine the conditioning regimen, enable relevant prophylactic measures and early intervention or contribute to avoid unnecessary or even harmful medication. Finally, it allows for genetic counseling and follow-up of at-risk family members. Identification of these patients in the clinical setting is challenging, as there is no consensus due to lack of evidence regarding the criteria defining the patients who should be tested for these conditions. In addition, even in cases with a strong suspicion of a MN with germline predisposition, no standard diagnostic algorithm is available. We present the first version of the Nordic recommendations for diagnostics, surveillance and management including considerations for allo-HSCT for patients and carriers of a germline mutation predisposing to the development of MNs.
  • Chattopadhyay, Subhayan; Zheng, Guoqiao; Sud, Amit; Yu, Hongyao; Sundquist, Kristina; Sundquist, Jan; Försti, Asta; Hemminki, Akseli; Houlston, Richard; Hemminki, Kari (2018)
    Background Although advances in the treatment of myeloid neoplasms have led to improved patient survival, this improvement has been accompanied by an increased risk of second primary cancer (ie, the risk of another cancer after myeloid neoplasia). We aimed to assess bi-directional associations between myeloid cancers and other cancers-ie, development of second primary cancer in patients who have previously had myeloid cancer, and risks of myeloid neoplasia in patients who have previously had another cancer-to provide insight into possible mechanisms beyond side-effects of treatment and shared risk factors. Methods Using the Swedish Family-Cancer Database, we identified 35 928 individuals with primary myeloid cancer, including myeloproliferative neoplasms, acute myeloid leukaemia, chronic myeloid leukaemia, and myelodysplastic syndrome diagnosed between 1958 and 2015. The Swedish Family-Cancer Database includes every individual registered as a resident in Sweden starting in 1932, with full parental history. The primary endpoint was the assessment of relative risks (RRs) for second primary cancer, which we performed using means of incidence rate ratios, regressed over a generalised Poisson model. Findings Between 1958 and 2015, overall relative risk of second primary cancers was significantly increased after acute myeloid leukaemia (RR 1.29, 95% CI 1.17-1.41), chronic myeloid leukaemia (1.52, 1.35-1.69), myelodysplastic syndrome (1.42, 1.26-1.59), and all myeloproliferative neoplasms (1.37, 1.30-1.43) relative to the incidence of these cancers as first primary cancer. With myeloid neoplasia as a second primary cancer, risks were significantly increased for acute myeloid leukaemia (1.57, 1.48-1.65), chronic myeloid leukaemia (1.26, 1.13-1.40), and myelodysplastic syndrome (1.54, 1.42-1.67) relative to the incidence of these myeloid neoplasms as first primary cancers. Relative risk of upper aerodigestive tract cancer, squamous cell skin cancer, and non-Hodgkin lymphoma as second primary cancers were increased after all four types of myeloid neoplasia relative to their incidence as first primary cancers. High risks of myelodysplastic syndrome and acute myeloid leukaemia as second primary cancers were found after haematological cancers (RRs between 5.08 and 10.04). Interpretation The relative risks of second primary cancer are important for the long-term management of patients with myeloid cancers. The bi-directional associations of myeloid cancers with many other cancers suggest a number of candidate mechanisms that might contribute to the development and aetiology of a second primary cancer. These mechanisms might include immune dysfunction or the effects of treatment, and these should be assessed in future investigations. Copyright (c) 2018 Elsevier Ltd. All rights reserved.
  • Zhang, Luyao; Hemminki, Otto; Chen, Tianhui; Yu, Hongyao; Zheng, Guoqiao; Chattopadhyay, Subhayan; Försti, Asta; Sundquist, Kristina; Sundquist, Jan; Hemminki, Kari (2019)
    While treatment for testicular cancer (TC) has become standardized after the 1980s with an associated significant improvement in patient survival, this has been accompanied by an increased risk of second primary cancers (SPCs). Patients were identified from the Swedish Cancer Registry spanning the years from 1980 to 2015, including 8788 individuals with primary TC and their SPCs. Relative risks (RRs) for SPC were calculated using the generalized Poisson regression model. SPCs were diagnosed in 9.4% of patients with TC and half of them were late onset cancers not common in the population in their 40s. Overall RR of SPCs (excluding second TC) was 1.30 (95%CI: 1.20-1.40), including high risks for seven solid cancers, non-Hodgkin lymphoma and leukemia. Second TC was the most common SPC and the RR of 17.19 (95%CI: 14.89-19.85) was the highest recorded. Cancers known to be fatal as first primary cancers were also fatal as SPC in TC patients. Survival at 30 years of follow-up was approximately 80% for TC patients without SPC but it decreased to 40% for patients with SPC. The unexpected finding that half of the identified SPCs were typical late onset cancers in the middle-aged population raises concerns that therapy may facilitate premature aging. The risks of SPC are clinically important for the long-term management of TC patients and the high-mortality calls for a future management strategy.
  • Savola, P.; Kelkka, T.; Rajala, H. L.; Kuuliala, A.; Kuuliala, K.; Eldfors, S.; Ellonen, P.; Lagstrom, S.; Lepisto, M.; Hannunen, T.; Andersson, E. I.; Khajuria, R. K.; Jaatinen, T.; Koivuniemi, R.; Repo, H.; Saarela, J.; Porkka, K.; Leirisalo-Repo, M.; Mustjoki, S. (2017)
    Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8(+) T-cell clones; in 20% (5/25) of patients CD8(+) T cells, but not CD4(+) T cells, harbour somatic mutations. In healthy controls (n = 20), only one mutation is identified in the CD8(+) T-cell pool. Mutations exist exclusively in the expanded CD8(+) effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8(+) T cells, which may have pathogenic significance for RA and other autoimmune diseases.
  • Ifversen, Marianne; Meisel, Roland; Sedlacek, Petr; Kalwak, Krzysztof; Sisinni, Luisa; Hutt, Daphna; Lehrnbecher, Thomas; Balduzzi, Adriana; Diesch, Tamara; Jarisch, Andrea; Gungor, Tayfun; Stein, Jerry; Yaniv, Isaac; Bonig, Halvard; Kuhlen, Michaela; Ansari, Marc; Nava, Tiago; Dalle, Jean-Hugues; Diaz-de-Heredia, Cristina; Trigoso, Eugenia; Falkenberg, Ulrike; Hartmann, Mihaela; Deiana, Marco; Canesi, Marta; Broggi, Chiara; Bertaina, Alice; Gibson, Brenda; Krivan, Gergely; Vettenranta, Kim; Matic, Toni; Buechner, Jochen; Lawitschka, Anita; Peters, Christina; Yesilipek, Akif; Yalcin, Koray; Lucchini, Giovanna; Bakhtiar, Shahrzad; Turkiewicz, Dominik; Niinimaki, Riitta; Wachowiak, Jacek; Cesaro, Simone; Dalissier, Arnaud; Corbacioglu, Selim; Willasch, Andre Manfred; Bader, Peter (2021)
    Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.