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239 results on '"Dufva, Olli"'

1. Tracing back primed resistance in cancer via sister cells

Author

Dai, Jun, Zheng, Shuyu, Falco, Matías M., Bao, Jie, Eriksson, Johanna, Pikkusaari, Sanna, Forstén, Sofia, Jiang, Jing, Wang, Wenyu, Gao, Luping, Perez-Villatoro, Fernando, Dufva, Olli, Saeed, Khalid, Wang, Yinyin, Amiryousefi, Ali, Färkkilä, Anniina, Mustjoki, Satu, Kauppi, Liisa, Tang, Jing, and Vähärautio, Anna

Published
2024
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3. High-throughput drug screening identifies SMAC mimetics as enhancers of NK-cell cytotoxicity in chronic myeloid leukemia

Author

Nygren, Petra, Bouhlal, Jonas, Jokinen, Emmi, Forsten, Sofia, Laajala, Essi, Dias, Diogo, Adnan-Awad, Shady, Ianevski, Aleksandr, Klievink, Jay, Lähteenmäki, Hanna, Kuusanmäki, Heikki, Myllymäki, Mikko, Kasanen, Tiina, Saeed, Khalid, Lee, Dean A., Hjorth-Hansen, Henrik, Aittokallio, Tero, Dufva, Olli, and Mustjoki, Satu

Published
2025
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4. Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation

Author

Huuhtanen, Jani, Adnan-Awad, Shady, Theodoropoulos, Jason, Forstén, Sofia, Warfvinge, Rebecca, Dufva, Olli, Bouhlal, Jonas, Dhapola, Parashar, Duàn, Hanna, Laajala, Essi, Kasanen, Tiina, Klievink, Jay, Ilander, Mette, Jaatinen, Taina, Olsson-Strömberg, Ulla, Hjorth-Hansen, Henrik, Burchert, Andreas, Karlsson, Göran, Kreutzman, Anna, Lähdesmäki, Harri, and Mustjoki, Satu

Published
2024
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6. Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia

Author

Kuusanmäki, Heikki, Dufva, Olli, Vähä-Koskela, Markus, Leppä, Aino-Maija, Huuhtanen, Jani, Vänttinen, Ida, Nygren, Petra, Klievink, Jay, Bouhlal, Jonas, Pölönen, Petri, Zhang, Qi, Adnan-Awad, Shady, Mancebo-Pérez, Cristina, Saad, Joseph, Miettinen, Juho, Javarappa, Komal K., Aakko, Sofia, Ruokoranta, Tanja, Eldfors, Samuli, Heinäniemi, Merja, Theilgaard-Mönch, Kim, Wartiovaara-Kautto, Ulla, Keränen, Mikko, Porkka, Kimmo, Konopleva, Marina, Wennerberg, Krister, Kontro, Mika, Heckman, Caroline A., and Mustjoki, Satu

Published
2023
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7. Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis

Author

Toledo, Marcelo A.S., Gatz, Malrun, Sontag, Stephanie, Gleixner, Karoline V., Eisenwort, Gregor, Feldberg, Kristina, Hamouda, Ahmed E.I., Kluge, Frederick, Guareschi, Riccardo, Rossetti, Giulia, Sechi, Antonio S., Dufva, Olli M.J., Mustjoki, Satu M., Maurer, Angela, Schüler, Herdit M., Goetzke, Roman, Braunschweig, Till, Kaiser, Anne, Panse, Jens, Jawhar, Mohamad, Reiter, Andreas, Hilberg, Frank, Ettmayer, Peter, Wagner, Wolfgang, Koschmieder, Steffen, Brümmendorf, Tim H., Valent, Peter, Chatain, Nicolas, and Zenke, Martin

Published
2021
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8. Single-cell characterization of anti-LAG-3 and anti-PD-1 combination treatment in patients with melanoma

Author

Huuhtanen, Jani, Kasanen, Henna, Peltola, Katriina, Lonnberg, Tapio, Glumoff, Virpi, Bruck, Oscar, Dufva, Olli, Peltonen, Karita, Vikkula, Johanna, Jokinen, Emmi, Ilander, Mette, Lee, Moon Hee, Makela, Siru, Nyakas, Marta, Li, Bin, Hernberg, Micaela, Bono, Petri, Lahdesmaki, Harri, Kreutzman, Anna, and Mustjoki, Satu

Subjects
Care and treatment, Methods, Combination drug therapy -- Methods, Immunotherapy -- Methods, Melanoma -- Care and treatment, Drug therapy, Combination -- Methods
Abstract

Introduction Even though immune checkpoint inhibitor therapies have revolutionized the treatment of metastatic melanoma, a majority of patients fail to achieve sustainable responses. As currently available immune checkpoint inhibitor therapies [...], BACKGROUND. Relatlimab plus nivolumab (anti-lymphocyte-activation gene 3 plus anti-programmed death 1 [anti- [LAG3.sup.+]anti-PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown. METHODS. We evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG-3+anti-PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCR[alpha][beta]-Seq) combined with other multiomics profiling. RESULTS. The highest LAG3 expression was noted in NK cells, Tregs, and [CD8.sup.+] T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy, resulting in an active phenotype. [LAG3.sup.+] Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding [CD8.sup.+] T cell clones gained a more cytotoxic and NK-like phenotype. CONCLUSION. Anti-LAG-3+anti-PD-1 therapy has profound effects on NK cells and Tregs in addition to [CD8.sup.+] T cells. TRIAL REGISTRATION. ClinicalTrials.gov (NCT01968109) FUNDING. Cancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS.

Published
2023
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9. Genome-scale screens identify factors regulating tumor cell responses to natural killer cells

Author

Sheffer, Michal, Lowry, Emily, Beelen, Nicky, Borah, Minasri, Amara, Suha Naffar-Abu, Mader, Chris C., Roth, Jennifer A., Tsherniak, Aviad, Freeman, Samuel S., Dashevsky, Olga, Gandolfi, Sara, Bender, Samantha, Bryan, Jordan G., Zhu, Cong, Wang, Li, Tariq, Ifrah, Kamath, Govinda M., Simoes, Ricardo De Matos, Dhimolea, Eugen, Yu, Channing, Hu, Yiguo, Dufva, Olli, Giannakis, Marios, Syrgkanis, Vasilis, Fraenkel, Ernest, Golub, Todd, Romee, Rizwan, Mustjoki, Satu, Culhane, Aedin C., Wieten, Lotte, and Mitsiades, Constantine S.

Published
2021
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10. Immunogenomic Landscape of Hematological Malignancies

Author

Dufva, Olli, Pölönen, Petri, Brück, Oscar, Keränen, Mikko A.I., Klievink, Jay, Mehtonen, Juha, Huuhtanen, Jani, Kumar, Ashwini, Malani, Disha, Siitonen, Sanna, Kankainen, Matti, Ghimire, Bishwa, Lahtela, Jenni, Mattila, Pirkko, Vähä-Koskela, Markus, Wennerberg, Krister, Granberg, Kirsi, Leivonen, Suvi-Katri, Meriranta, Leo, Heckman, Caroline, Leppä, Sirpa, Nykter, Matti, Lohi, Olli, Heinäniemi, Merja, and Mustjoki, Satu

Published
2020
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11. Disruption of KLHL6 Fuels Oncogenic Antigen Receptor Signaling in B-cell Lymphoma

Author

Meriranta, Leo, primary, Sorri, Selma, additional, Huse, Kanutte, additional, Liu, Xiaonan, additional, Spasevska, Ivana, additional, Zafar, Sadia, additional, Chowdhury, Iftekhar, additional, Dufva, Olli, additional, Sahlberg, Eerika, additional, Tandaric, Luka, additional, Karjalainen-Lindsberg, Marja-Liisa, additional, Hyytiainen, Marko, additional, Varjosalo, Markku, additional, Myklebust, June H., additional, and Leppa, Sirpa, additional

Published
2024
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15. IFN-[alpha] with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia

Author

Huuhtanen, Jani, Ilander, Mette, Yadav, Bhagwan, Dufva, Olli M.J., Lahteenmaki, Hanna, Kasanen, Tiina, Klievink, Jay, Olsson-Stromberg, Ulla, Stentoft, Jesper, Richter, Johan, Koskenvesa, Perttu, Hoglund, Martin, Soderlund, Stina, Dreimane, Arta, Porkka, Kimmo, Gedde-Dahl, Tobias, Gjertsen, Bjorn T., Stenke, Leif, Myhr-Eriksson, Kristina, Markevarn, Berit, Lubking, Anna, Dimitrijevic, Andreja, Udby, Lene, Bjerrum, Ole Weis, Hjorth-Hansen, Henrik, and Mustjoki, Satu

Subjects
Drug therapy, Physiological aspects, Dosage and administration, Methods, Health aspects, Combination chemotherapy -- Methods -- Physiological aspects, Immune system -- Health aspects, Chronic myeloid leukemia -- Drug therapy -- Physiological aspects, Dasatinib -- Dosage and administration -- Physiological aspects, Interferon alpha -- Dosage and administration -- Physiological aspects, Chemotherapy, Combination -- Methods -- Physiological aspects
Abstract

Introduction Currently, the ultimate therapeutic goal in patients with chronic-phase chronic myeloid leukemia (CP-CML) is to achieve deep molecular remission, which would allow the discontinuation of tyrosine kinase inhibitor (TKI) [...], In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-[alpha] is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-[alpha] in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR[beta] sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and [CD8.sup.+] T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of [CD8.sup.+] recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-[alpha] reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-[alpha] had costimulatory effects on TCR signaling. Our work supports the combination of IFN-[alpha] with TKI therapy, as IFN-[alpha] broadens the immune repertoire and restores immunological function.

Published
2022
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16. Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia

Author

Kämpjärvi, Kati, Järvinen, Tiina M, Heikkinen, Tuomas, Ruppert, Amy S, Senter, Leigha, Hoag, Kevin W, Dufva, Olli, Kontro, Mika, Rassenti, Laura, Hertlein, Erin, Kipps, Thomas J, Porkka, Kimmo, Byrd, John C, de la Chapelle, Albert, and Vahteristo, Pia

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer Genomics, Lymphoma, Human Genome, Genetics, Rare Diseases, Clinical Research, Lymphatic Research, Cancer, Hematology, 2.1 Biological and endogenous factors, Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mediator Complex, Middle Aged, Molecular Sequence Data, Mutation, Prognosis, Chronic lymphocytic leukemia, MED12, somatic mutation, cancer genetics, prognosis, Oncology and carcinogenesis
Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. We performed systematic database search and identified highly specific MED12 mutations in CLL patients. To study this further, we collected three independent sample series comprising over 700 CLL samples and screened MED12 exons 1 and 2 by direct sequencing. Mutations were identified at significant frequency in all three series with a combined mutation frequency of 5.2% (37/709). Positive mutation status was found to be associated with unmutated IGHV and ZAP70 expression, which are well-known poor prognosis markers in CLL. Our results recognize CLL as the first extrauterine cancer type where 5'terminus of MED12 is mutated at significant frequency. Functional analyses have shown that these mutations lead to dissociation of Cyclin C-CDK8/19 from the core Mediator and to the loss of Mediator-associated CDK kinase activity. Additional studies on the role of MED12 mutation status as a putative prognostic factor as well as mutations' exact tumorigenic mechanism in CLL are warranted.

Published
2015

17. Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers

Author

Dufva, Olli, primary, Gandolfi, Sara, additional, Huuhtanen, Jani, additional, Dashevsky, Olga, additional, Duàn, Hanna, additional, Saeed, Khalid, additional, Klievink, Jay, additional, Nygren, Petra, additional, Bouhlal, Jonas, additional, Lahtela, Jenni, additional, Näätänen, Anna, additional, Ghimire, Bishwa R., additional, Hannunen, Tiina, additional, Ellonen, Pekka, additional, Lähteenmäki, Hanna, additional, Rumm, Pauliina, additional, Theodoropoulos, Jason, additional, Laajala, Essi, additional, Härkönen, Jouni, additional, Pölönen, Petri, additional, Heinäniemi, Merja, additional, Hollmén, Maija, additional, Yamano, Shizuka, additional, Shirasaki, Ryosuke, additional, Barbie, David A., additional, Roth, Jennifer A., additional, Romee, Rizwan, additional, Sheffer, Michal, additional, Lähdesmäki, Harri, additional, Lee, Dean A., additional, De Matos Simoes, Ricardo, additional, Kankainen, Matti, additional, Mitsiades, Constantine S., additional, and Mustjoki, Satu, additional

Published
2023
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18. Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation

Author

Huuhtanen, Jani, primary, Adnan-Awad, Shady, additional, Theodoropoulos, Jason, additional, Forstén, Sofia, additional, Warfvinge, Rebecca, additional, Dufva, Olli, additional, Bouhlal, Jonas, additional, Dhapola, Parashar, additional, Duàn, Hanna, additional, Laajala, Essi, additional, Kasanen, Tiina, additional, Klievink, Jay, additional, Ilander, Mette, additional, Jaatinen, Taina, additional, Olsson-Strömberg, Ulla, additional, Hjorth-Hansen, Henrik, additional, Burchert, Andreas, additional, Karlsson, Göran, additional, Kreutzman, Anna, additional, Lähdesmäki, Harri, additional, and Mustjoki, Satu, additional

Published
2023
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20. P-182 Natural killer cells are active against myeloma cells with loss of tumor suppressor genes

Author

Dashevsky, Olga, primary, Gandolfi, Sara, additional, Dufva, Olli, additional, de Matos Simoes, Ricardo, additional, Huuhtanen, Jani, additional, Barwick, Benjamin, additional, Shirasaki, Ryosuke, additional, Sheffer, Michal, additional, Culhane, Aedin, additional, Licht, Jonathan, additional, Liacos, Christine-Ivy, additional, Terpos, Evangelos, additional, Kastritis, Efstathios, additional, Dimopoulos, Meletios, additional, Vazquez, Francisca, additional, Boise, Lawrence, additional, Kankainen, Matti, additional, Mustjoki, Satu, additional, and Mitsiades, Constantine, additional

Published
2023
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22. P1228: GENOME-WIDE CRISPR-CAS9 SCREENING IDENTIFIES THERAPEUTIC TARGETS FOR MATURE T-CELL MALIGNANCIES

Author

Timonen, Sanna, primary, Rebecca Gasparini, Vanessa, additional, Piekkari, Ella, additional, Dufva, Olli, additional, Awad, Shady, additional, Akimov, Yevhen, additional, von Jan, Jana, additional, Braun, Till, additional, Ianevski, Aleksandr, additional, Kankainen, Matti, additional, Klievink, Jay, additional, Herling, Marco, additional, Aittokallio, Tero, additional, and Mustjoki, Satu, additional

Published
2023
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23. P409: BCL-2/BCL-XL INHIBITION INDUCES APOPTOSIS AND CIRCUMVENTS VENETOCLAX RESISTANCE IN TP53-MUTATED ACUTE MYELOID LEUKEMIA

Author

Vänttinen, Ida, primary, Kytölä, Sari, additional, Dufva, Olli, additional, Hellesøy, Monica, additional, Gullaksen, Stein-Erik, additional, Ruokoranta, Tanja, additional, Brück, Oscar, additional, Siitonen, Sanna, additional, Ettala, Pia, additional, Pyörälä, Marja, additional, Rimpilainen, Johanna, additional, Siitonen, Timo, additional, Tore Gjertsen, Bjorn, additional, Heckman, Caroline, additional, Kuusanmäki, Heikki, additional, and Kontro, Mika, additional

Published
2023
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24. Ex vivo venetoclax sensitivity testing predicts treatment response in acute myeloid leukemia

Author

Kuusanmäki, Heikki, Kytölä, Sari, Vänttinen, Ida, Ruokoranta, Tanja, Ranta, Amanda, Huuhtanen, Jani, Suvela, Minna, Parsons, Alun, Holopainen, Annasofia, Partanen, Anu, Kuusisto, Milla E.L., Koskela, Sirpa, Räty, Riikka, Itälä-Remes, Maija, Västrik, Imre, Dufva, Olli, Siitonen, Sanna, Porkka, Kimmo, Wennerberg, Krister, Heckman, Caroline A., Ettala, Pia, Pyörälä, Marja, Rimpiläinen, Johanna, Siitonen, Timo, Kontro, Mika, Kuusanmäki, Heikki, Kytölä, Sari, Vänttinen, Ida, Ruokoranta, Tanja, Ranta, Amanda, Huuhtanen, Jani, Suvela, Minna, Parsons, Alun, Holopainen, Annasofia, Partanen, Anu, Kuusisto, Milla E.L., Koskela, Sirpa, Räty, Riikka, Itälä-Remes, Maija, Västrik, Imre, Dufva, Olli, Siitonen, Sanna, Porkka, Kimmo, Wennerberg, Krister, Heckman, Caroline A., Ettala, Pia, Pyörälä, Marja, Rimpiläinen, Johanna, Siitonen, Timo, and Kontro, Mika

Abstract

The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory AML. Ex vivo drug sensitivity testing may correlate with outcomes, but its prospective predictive value remains unexplored. Here we report the results of the first stage of the prospective phase II VenEx trial evaluating the utility and predictiveness of venetoclax sensitivity testing using different cell culture conditions and cell viability assays in patients receiving venetoclax-azacitidine. Participants with de novo AML ineligible for intensive chemotherapy, relapsed or refractory AML, or secondary AML were included. The primary endpoint was the treatment response in participants showing ex vivo sensitivity and the key secondary endpoints were the correlation of sensitivity with responses and survival. Venetoclax sensitivity testing was successful in 38/39 participants. Experimental conditions significantly influenced the predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved a treatment response. The median survival was significantly longer for participants who were ex vivo-sensitive to venetoclax (14.6 months for venetoclax-sensitive patients vs. 3.5 for venetoclax-insensitive patients, P<0.001). This analysis illustrates the feasibility of integrating drug-response profiling into clinical practice and demonstrates excellent predictivity.

Published
2023

25. Abstract 667: Single-cell functional genomics of natural killer cell evasion by tumor cells

Author

Dufva, Olli, primary, Gandolfi, Sara, additional, Huuhtanen, Jani, additional, Dashevsky, Olga, additional, Saeed, Khalid, additional, Klievink, Jay, additional, Nygren, Petra, additional, Bouhlal, Jonas, additional, Lahtela, Jenni, additional, Näätänen, Anna, additional, Ghimire, Bishwa, additional, Hannunen, Tiina, additional, Ellonen, Pekka, additional, Duàn, Hanna, additional, Theodoropoulos, Jason, additional, Laajala, Essi, additional, Härkönen, Jouni, additional, Pölönen, Petri, additional, Heinäniemi, Merja, additional, Yamano, Shizuka, additional, Shirasaki, Ryosuke, additional, Barbie, David, additional, Roth, Jennifer, additional, Romee, Rizwan, additional, Sheffer, Michal, additional, Lähdesmäki, Harri, additional, Lee, Dean A., additional, Simoes, Ricardo De Matos, additional, Kankainen, Matti, additional, Mitsiades, Constantine S., additional, and Mustjoki, Satu, additional

Published
2023
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26. Supplementary Data from Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, primary, Brück, Oscar, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Hellesøy, Monica, primary, Kuusanmäki, Heikki, primary, Dufva, Olli, primary, Kankainen, Matti, primary, Eldfors, Samuli, primary, Potdar, Swapnil, primary, Saarela, Jani, primary, Turunen, Laura, primary, Parsons, Alun, primary, Västrik, Imre, primary, Kivinen, Katja, primary, Saarela, Janna, primary, Räty, Riikka, primary, Lehto, Minna, primary, Wolf, Maija, primary, Gjertsen, Bjorn Tore, primary, Mustjoki, Satu, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Heckman, Caroline A., primary, Kallioniemi, Olli, primary, and Porkka, Kimmo, primary

Published
2023
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27. Supplementary Tables from Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, primary, Brück, Oscar, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Hellesøy, Monica, primary, Kuusanmäki, Heikki, primary, Dufva, Olli, primary, Kankainen, Matti, primary, Eldfors, Samuli, primary, Potdar, Swapnil, primary, Saarela, Jani, primary, Turunen, Laura, primary, Parsons, Alun, primary, Västrik, Imre, primary, Kivinen, Katja, primary, Saarela, Janna, primary, Räty, Riikka, primary, Lehto, Minna, primary, Wolf, Maija, primary, Gjertsen, Bjorn Tore, primary, Mustjoki, Satu, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Heckman, Caroline A., primary, Kallioniemi, Olli, primary, and Porkka, Kimmo, primary

Published
2023
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28. Data from Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, primary, Brück, Oscar, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Hellesøy, Monica, primary, Kuusanmäki, Heikki, primary, Dufva, Olli, primary, Kankainen, Matti, primary, Eldfors, Samuli, primary, Potdar, Swapnil, primary, Saarela, Jani, primary, Turunen, Laura, primary, Parsons, Alun, primary, Västrik, Imre, primary, Kivinen, Katja, primary, Saarela, Janna, primary, Räty, Riikka, primary, Lehto, Minna, primary, Wolf, Maija, primary, Gjertsen, Bjorn Tore, primary, Mustjoki, Satu, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Heckman, Caroline A., primary, Kallioniemi, Olli, primary, and Porkka, Kimmo, primary

Published
2023
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29. Supplementary Figures from Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, primary, Brück, Oscar, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Hellesøy, Monica, primary, Kuusanmäki, Heikki, primary, Dufva, Olli, primary, Kankainen, Matti, primary, Eldfors, Samuli, primary, Potdar, Swapnil, primary, Saarela, Jani, primary, Turunen, Laura, primary, Parsons, Alun, primary, Västrik, Imre, primary, Kivinen, Katja, primary, Saarela, Janna, primary, Räty, Riikka, primary, Lehto, Minna, primary, Wolf, Maija, primary, Gjertsen, Bjorn Tore, primary, Mustjoki, Satu, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Heckman, Caroline A., primary, Kallioniemi, Olli, primary, and Porkka, Kimmo, primary

Published
2023
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30. Ex vivo venetoclax sensitivity testing predicts treatment response in acute myeloid leukemia

Author

Kuusanmäki, Heikki, primary, Kytölä, Sari, additional, Vänttinen, Ida, additional, Ruokoranta, Tanja, additional, Ranta, Amanda, additional, Huuhtanen, Jani, additional, Suvela, Minna, additional, Parsons, Alun, additional, Holopainen, Annasofia, additional, Partanen, Anu, additional, Kuusisto, Milla E.L., additional, Koskela, Sirpa, additional, Räty, Riikka, additional, Itälä-Remes, Maija, additional, Västrik, Imre, additional, Dufva, Olli, additional, Siitonen, Sanna, additional, Porkka, Kimmo, additional, Wennerberg, Krister, additional, Heckman, Caroline A., additional, Ettala, Pia, additional, Pyörälä, Marja, additional, Rimpiläinen, Johanna, additional, Siitonen, Timo, additional, and Kontro, Mika, additional

Published
2022
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31. Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia

Author

Kuusanmäki, Heikki, primary, Dufva, Olli, additional, Vähä-Koskela, Markus, additional, Leppä, Aino-Maija, additional, Huuhtanen, Jani, additional, Vänttinen, Ida Maria, additional, Nygren, Petra Johanna, additional, Klievink, Jay, additional, Bouhlal, Jonas Otto Vilhelm, additional, Pölönen, Petri, additional, Zhang, Qi, additional, Adnan Awad, Shady, additional, Mancebo-Pérez, Cristina, additional, Saad, Joseph, additional, Miettinen, Juho J., additional, Javarappa, Komal Kumar, additional, Aakko, Sofia, additional, Ruokoranta, Tanja, additional, Eldfors, Samuli, additional, Heinäniemi, Merja, additional, Theilgaard-Mönch, Kim, additional, Wartiovaara-Kautto, Ulla, additional, Keränen, Mikko A I, additional, Porkka, Kimmo, additional, Konopleva, Marina, additional, Wennerberg, Krister, additional, Kontro, Mika, additional, Heckman, Caroline A., additional, and Mustjoki, Satu, additional

Published
2022
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33. Functional immunogenomics in hematological malignancies

Author

Dufva, Olli, University of Helsinki, Faculty of Medicine, Doctoral Program in Clinical Research, Helsingin yliopisto, lääketieteellinen tiedekunta, Kliininen tohtoriohjelma, Helsingfors universitet, medicinska fakulteten, Doktorandprogrammet i klinisk forskning, Gill, Saar, Mustjoki, Satu, and Keränen, Mikko

Subjects
lääketiede
Abstract

Cancer immunotherapy, or activating immunity against malignant cells, is a promising treatment option in hematological malignancies. More effective immunotherapies could be applied with higher precision if we better understood how immune properties depend on the cancer type and genetic makeup of the cancer cells, which mechanisms determine whether a cancer cell is eliminated by immune cells, and how to pharmacologically exploit such mechanisms. Functional genomics provides tools such as gene expression profiling and genetic perturbation screens to study immunological processes in cancer. This work aimed to discover connections between the immune properties and molecular subtypes of blood cancers (study I), the genetic basis and drug sensitivity profile of aggressive natural killer (NK) cell leukemia (study II), resistance mechanisms of lymphocyte cytotoxicity (studies III and IV), and combination treatments with chimeric antigen receptor (CAR) T cell therapy (study IV) using functional genomics and high-throughput drug screening. Genomic data from over 10,000 blood cancer patients revealed genetic determinants of immune infiltration such as a myelodysplastic syndrome-like subtype in acute myeloid leukemia (AML), regulation of antigen presentation by DNA methylation, and immune features typical for certain cancer types, such as the inhibitory immune regulator VISTA in myeloid malignancies and cancer-germline antigens in multiple myeloma. By exposing blood cancer cells to NK cells, we found differences in NK cell activation responses and sensitivity to NK cells depending on the cancer type, with AML being more susceptible than B cell acute lymphoblastic leukemia. Genome-scale CRISPR screens revealed cancer cell-intrinsic regulators of sensitivity to NK cells, explaining observed differences in sensitivity and highlighting new regulators such as adhesion molecules SPN, SELPLG, and CD44 and transcriptional regulators MYB, YTHDF2, and CMIP. Out of over 500 oncology drugs, a class of drugs known as SMAC mimetics sensitized leukemia cells to killing by CAR T cells. Somatic mutations in STAT3, DDX3X, RAS-MAPK genes and several epigenetic modifiers constituted the genetic basis of aggressive NK cell leukemia. JAK and BCL2 family inhibitors emerged as potential therapies in NK cell malignancies. The findings suggest that considering molecular subtypes of cancer may be useful in the search for optimal immunotherapies, and provide leads on genetic mechanisms and drugs that could facilitate development of new precision medicine and immunotherapy approaches in hematological malignancies. Syövän immunoterapia eli elimistön immuunipuolustuksen aktivoiminen pahanlaatuisia soluja vastaan on lupaava hoitomuoto verisyövissä. Immunoterapioita voitaisiin tehostaa ja kohdentaa paremmin ymmärtämällä miten immunologiset ominaisuudet riippuvat syöpäsolujen perimän muutoksista ja eroavat syöpätyyppien välillä, mitkä mekanismit määrittävät syöpäsolun herkkyyden immuunisoluille, ja miten näitä mekanismeja voitaisiin hyödyntää lääkkeiden avulla. Funktionaalinen genomiikka tarjoaa geeniekspressioprofiloinnin ja funktionaalisten geeniseulontojen kaltaisia työkaluja näiden syöpäimmunologian kysymysten tutkimukseen. Tutkimuksen tavoitteena oli selvittää yhteyksiä immunologisten piirteiden ja verisyöpien molekyylitason alatyyppien kanssa (osatyö I), aggressiivisen NK-soluleukemian geneettinen perusta ja lääkeherkkyysprofiili (osatyö II), vastustusmekanismeja imusoluvälitteiselle solutapolle (osatyöt III ja IV) ja yhdistelmälääkehoitoja CAR-T-soluhoidoille (osatyö IV) käyttäen funktionaalista genomiikkaa ja lääkkeiden tehoseulontaa. Yli 10 000 verisyöpäpotilaan genomitiedosta paljastui immuunisolujen määrään liittyviä tekijöitä kuten myelodysplastisen oireyhtymän kaltaisen alatyypin akuutissa myeloisessa leukemiassa (AML), DNA:n metylaation vaikutus antigeenien esittelyyn, sekä tietyille syöpätyypeille ominaisia immunologisia piirteitä, kuten T-solujen toimintaa estävä VISTA myeloisissa maligniteeteissa ja syöpä-iturata-antigeenit multippelissa myeloomassa. Altistamalla verisyöpäsoluja NK-soluille havaitsimme, että syöpäsolujen tyyppi vaikutti sekä NK-soluissa tapahtuvaan aktivaatiovasteeseen että syöpäsolujen herkkyyteen NK soluille: AML-solut olivat herkempiä kuin B-soluisen akuutin lymfoblastileukemian solut. Perimänlaajuiset CRISPR-seulonnat verisyöpäsolulinjoissa paljastivat herkkyyseroja selittäviä syöpäsolujen sisäisiä mekanismeja ja nostivat esiin uusia NK-soluherkkyyden säätelijöitä, kuten solujen kiinnittymismolekyylit SPN, SELPLG ja CD44 sekä geenien ilmentymisen säätelijät MYB, YTHDF2, ja CMIP. Somaattiset mutaatiot STAT3- ja DDX3X-geeneissä, RAS-MAPK-signaloinnissa sekä monissa epigeneettisissä säätelijöissä muodostivat aggressiivisen NK-soluleukemian geneettisen perustan, ja lääkeherkkyysseulonnalla havaittiin JAK-estäjät ja BCL2-perheen estäjät mahdollisina hoitoina. Yli 500 syöpälääkkeestä SMAC-mimeeteiksi kutsuttu lääkeryhmän herkisti leukemiasoluja CAR-T-soluille. Löydösten perusteella syövän molekyylitason alatyyppien huomioiminen voi olla hyödyksi optimaalisten immunoterapioiden etsinnässä. Työssä osoitetut geneettiset mekanismit ja lääkkeet voisivat auttaa uusien täsmähoitojen ja immunoterapioiden kehittämisessä verisyöpiin.

Published
2022

35. Single-Cell Functional Genomics of Natural Killer Cell Interaction with Blood Cancers

Author

Dufva, Olli, primary, Gandolfi, Sara, additional, Huuhtanen, Jani, additional, Dashevsky, Olga, additional, Saeed, Khalid, additional, Klievink, Jay, additional, Nygren, Petra Johanna, additional, Bouhlal, Jonas, additional, Lahtela, Jenni, additional, Näätänen, Anna, additional, Ghimire, Bishwa, additional, Hannunen, Tiina, additional, Ellonen, Pekka, additional, Duàn, Hanna, additional, Theodoropoulos, Jason, additional, Laajala, Essi, additional, Häkkinen, Aino, additional, Härkönen, Jouni, additional, Pölönen, Petri, additional, Heinäniemi, Merja, additional, Yamano, Shizuka, additional, Shirasaki, Ryosuke, additional, Barbie, David, additional, Roth, Jennifer A., additional, Romee, Rizwan, additional, Sheffer, Michal, additional, Lähdesmäki, Harri, additional, Lee, Dean Anthony, additional, De Matos Simoes, Ricardo, additional, Kankainen, Matti, additional, Mitsiades, Constantine S., additional, and Mustjoki, Satu, additional

Published
2022
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36. Erythroid/Megakaryocytic Differentiation Confers BCL-XL Dependency and Venetoclax Resistance in Acute Myeloid Leukemia

Author

Dufva, Olli, primary, Kuusanmäki, Heikki, additional, Vaha-Koskela, Markus, additional, Leppä, Aino-Maija, additional, Huuhtanen, Jani, additional, Vänttinen, Ida, additional, Nygren, Petra Johanna, additional, Klievink, Jay, additional, Bouhlal, Jonas, additional, Pölönen, Petri, additional, Zhang, Qi, additional, Awad, Shady Adnan, additional, Mancebo, Cristina, additional, Saad, Joseph, additional, Miettinen, Juho J., additional, Javarappa, Komal Kumar, additional, Aakko, Sofia, additional, Ruokoranta, Tanja, additional, Eldfors, Samuli, additional, Heinäniemi, Merja, additional, Wartiovaara-Kautto, Ulla, additional, Konopleva, Marina, additional, Keränen, Mikko A, additional, Porkka, Kimmo, additional, Wennerberg, Krister, additional, Kontro, Mika, additional, Heckman, Caroline A., additional, and Mustjoki, Satu, additional

Published
2022
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37. Integrated High-Throughput Drug Profiling and CRISPR Screening Identify Novel Pathway Vulnerabilities of Leukemic Stem Cells in Chronic Myeloid Leukemia

Author

Awad, Shady Adnan, primary, Dufva, Olli, additional, Klievink, Jay, additional, Karjalainen, Ella, additional, Ianevski, Aleksandr, additional, Pietarinen, Paavo, additional, Kim, Daehong, additional, Potdar, Swapnil, additional, Wolf, Maija, additional, Lotfi, Kourosh, additional, Aittokallio, Tero, additional, Wennerberg, Krister, additional, Porkka, Kimmo, additional, and Mustjoki, Satu, additional

Published
2022
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38. A Comprehensive, Multiomics Analysis of Natural Killer-Cell Malignancies

Author

Nygren, Petra Johanna, primary, Häkkinen, Aino, additional, Kim, Daehong, additional, Jarvinen, Timo, additional, Ishida, Fumihiro, additional, Bortoluzzi, Stefania, additional, Binatti, Andrea, additional, Gasparini, Vanessa Rebecca, additional, Zambello, Renato, additional, Myllymäki, Mikko, additional, Ogawa, Seishi, additional, Okuno, Yusuke, additional, Kimura, Hiroshi, additional, Chan, John, additional, Dufva, Olli, additional, Mustjoki, Satu, additional, and Kankainen, Matti, additional

Published
2022
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39. 1006 Single-cell functional genomics of natural killer cell evasion in blood cancers

Author

Dufva, Olli, primary, Gandolfi, Sara, additional, Huuhtanen, Jani, additional, Dashevsky, Olga, additional, Saeed, Khalid, additional, Klievink, Jay, additional, Nygren, Petra, additional, Bouhlal, Jonas, additional, Lahtela, Jenni, additional, Näätänen, Anna, additional, Ghimire, Bishwa, additional, Hannunen, Tiina, additional, Ellonen, Pekka, additional, Duàn, Hanna, additional, Theodoropoulos, Jason, additional, Laajala, Essi, additional, Härkönen, Jouni, additional, Pölönen, Petri, additional, Heinäniemi, Merja, additional, Yamano, Shizuka, additional, Shirasaki, Ryosuke, additional, Barbie, David, additional, Roth, Jennifer, additional, Romee, Rizwan, additional, Sheffer, Michal, additional, Lähdesmäki, Harri, additional, Lee, Dean, additional, Simoes, Ricardo De Matos, additional, Kankainen, Matti, additional, Mitsiades, Constantine, additional, and Mustjoki, Satu, additional

Published
2022
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40. IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia

Author

Huuhtanen, Jani, primary, Ilander, Mette, additional, Yadav, Bhagwan, additional, Dufva, Olli M.J., additional, Lähteenmäki, Hanna, additional, Kasanen, Tiina, additional, Klievink, Jay, additional, Olsson-Strömberg, Ulla, additional, Stentoft, Jesper, additional, Richter, Johan, additional, Koskenvesa, Perttu, additional, Höglund, Martin, additional, Söderlund, Stina, additional, Dreimane, Arta, additional, Porkka, Kimmo, additional, Gedde-Dahl, Tobias, additional, Gjertsen, Björn T., additional, Stenke, Leif, additional, Myhr-Eriksson, Kristina, additional, Markevärn, Berit, additional, Lübking, Anna, additional, Dimitrijevic, Andreja, additional, Udby, Lene, additional, Bjerrum, Ole Weis, additional, Hjorth-Hansen, Henrik, additional, and Mustjoki, Satu, additional

Published
2022
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41. Single-cell functional genomics of natural killer cell evasion in blood cancers

Author

Dufva, Olli, primary, Gandolfi, Sara, additional, Huuhtanen, Jani, additional, Dashevsky, Olga, additional, Saeed, Khalid, additional, Klievink, Jay, additional, Nygren, Petra, additional, Bouhlal, Jonas, additional, Lahtela, Jenni, additional, Näätänen, Anna, additional, Ghimire, Bishwa R, additional, Hannunen, Tiina, additional, Ellonen, Pekka, additional, Duàn, Hanna, additional, Theodoropoulos, Jason, additional, Laajala, Essi, additional, Härkönen, Jouni, additional, Pölönen, Petri, additional, Heinäniemi, Merja, additional, Yamano, Shizuka, additional, Shirasaki, Ryosuke, additional, Barbie, David, additional, Roth, Jennifer, additional, Romee, Rizwan, additional, Sheffer, Michal, additional, Lähdesmäki, Harri, additional, Lee, Dean A., additional, De Matos Simoes, Ricardo, additional, Kankainen, Matti, additional, Mitsiades, Constantine S, additional, and Mustjoki, Satu, additional

Published
2022
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42. Tracing back primed resistance in cancer via sister cells

Author

Dai, Jun, primary, Zheng, Shuyu, additional, Falco, Matías M., additional, Bao, Jie, additional, Eriksson, Johanna, additional, Perez-Villatoro, Fernando, additional, Färkkilä, Anniina, additional, Dufva, Olli, additional, Saeed, Khalid, additional, Mustjoki, Satu, additional, Wang, Yinyin, additional, Amiryousefi, Ali, additional, Tang, Jing, additional, and Vähärautio, Anna, additional

Published
2022
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43. Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, Kumar, Ashwini, Brück, Oscar, Kontro, Mika, Yadav, Bhagwan, Hellesøy, Monica, Kuusanmäki, Heikki, Dufva, Olli, Kankainen, Matti, Eldfors, Samuli, Potdar, Swapnil, Saarela, Jani, Turunen, Laura, Parsons, Alun, Västrik, Imre, Kivinen, Katja, Saarela, Janna, Räty, Riikka, Lehto, Minna, Wolf, Maija, Gjertsen, Bjorn Tore, Mustjoki, Satu, Aittokallio, Tero, Wennerberg, Krister, Heckman, Caroline A., Kallioniemi, Olli, Porkka, Kimmo, Malani, Disha, Kumar, Ashwini, Brück, Oscar, Kontro, Mika, Yadav, Bhagwan, Hellesøy, Monica, Kuusanmäki, Heikki, Dufva, Olli, Kankainen, Matti, Eldfors, Samuli, Potdar, Swapnil, Saarela, Jani, Turunen, Laura, Parsons, Alun, Västrik, Imre, Kivinen, Katja, Saarela, Janna, Räty, Riikka, Lehto, Minna, Wolf, Maija, Gjertsen, Bjorn Tore, Mustjoki, Satu, Aittokallio, Tero, Wennerberg, Krister, Heckman, Caroline A., Kallioniemi, Olli, and Porkka, Kimmo

Abstract

We generated ex vivo drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identification of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommen-dations, providing a paradigm for individualized implementation of functional precision cancer medicine.

Published
2022

44. Targeting Apoptosis Pathways With BCL2 and MDM2 Inhibitors in Adult B-cell Acute Lymphoblastic Leukemia

Author

Hohtari, Helena, primary, Kankainen, Matti, additional, Adnan-Awad, Shady, additional, Yadav, Bhagwan, additional, Potdar, Swapnil, additional, Ianevski, Aleksandr, additional, Dufva, Olli, additional, Heckman, Caroline, additional, Sexl, Veronika, additional, Kytölä, Soili, additional, Mustjoki, Satu, additional, and Porkka, Kimmo, additional

Published
2022
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45. Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, additional, Brück, Oscar, additional, Kontro, Mika, additional, Yadav, Bhagwan, additional, Hellesøy, Monica, additional, Kuusanmäki, Heikki, additional, Dufva, Olli, additional, Kankainen, Matti, additional, Eldfors, Samuli, additional, Potdar, Swapnil, additional, Saarela, Jani, additional, Turunen, Laura, additional, Parsons, Alun, additional, Västrik, Imre, additional, Kivinen, Katja, additional, Saarela, Janna, additional, Räty, Riikka, additional, Lehto, Minna, additional, Wolf, Maija, additional, Gjertsen, Bjorn Tore, additional, Mustjoki, Satu, additional, Aittokallio, Tero, additional, Wennerberg, Krister, additional, Heckman, Caroline A., additional, Kallioniemi, Olli, additional, and Porkka, Kimmo, additional

Published
2021
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46. Single-Cell Characterization of the Immune and Leukemic Cells Following Anti-TIM3 and Hypomethylating Agent Combination Therapy in Patients with AML or MDS

Author

Huuhtanen, Jani, primary, Brück, Oscar, additional, Peltonen, Karita, additional, Kreutzman, Anna, additional, Dufva, Olli, additional, Kankainen, Matti, additional, Ilander, Mette, additional, Lähteenmäki, Hanna, additional, Kasanen, Tiina, additional, Klievink, Jay, additional, Kontro, Mika, additional, Orlando, Elena J, additional, Cremasco, Viviana, additional, Wagner, Joel, additional, Pelletier, Marc, additional, Lähdesmäki, Harri, additional, Sabatos-Peyton, Catherine A., additional, Rinne, Mikael L., additional, Porkka, Kimmo, additional, and Mustjoki, Satu, additional

Published
2021
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48. OAB-019: CRISPR screens with single-cell transcriptome readout reveal potential mechanisms of response to natural killer cell treatment in multiple myeloma

Author

Gandolfi, Sara, primary, Dufva, Olli, additional, Huuhtanen, Jani, additional, Dashevsky, Olga, additional, Klievink, Jay, additional, Bouhlal, Jonas, additional, Scheffer, Michal, additional, Kankainen, Matti, additional, Simoes, Ricardo De Matos, additional, Mitsiades, Constantine, additional, and Mustjoki, Satu, additional

Published
2021
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50. Single-Cell Analysis of Immune Recognition in Chronic Myeloid Leukemia Patients Following Tyrosine Kinase Inhibitor Discontinuation

Author

Huuhtanen, Jani, Adnan-Awad, Shady, Theodoropoulos, Jason, Forstén, Sofia, Warfvinge, Rebecca, Dufva, Olli, Bouhlal, Jonas, Dhapola, Parashar, Duàn, Hanna, Laajala, Essi, Kasanen, Tiina, Klievink, Jay, Ilander, Mette, Jaatinen, Taina, Olsson-Strömberg, Ulla, Hjorth-Hansen, Henrik, Burchert, Andreas, Karlsson, Göran, Kreutzman, Anna, Lähdesmäki, Harri, and Mustjoki, Satu

Published
2023
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