publications

selected publications

1. Immunogenomic Landscape of Hematological Malignancies

   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

   Cancer Cell Jul 2020

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   Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-γ response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.

2. Integrated drug profiling and CRISPR screening identify essential pathways for CAR T-cell cytotoxicity

   Dufva, Olli, Koski, Jan, Maliniemi, Pilvi, Ianevski, Aleksandr, Klievink, Jay, Leitner, Judith, Pölönen, Petri, Hohtari, Helena, Saeed, Khalid, Hannunen, Tiina, Ellonen, Pekka, Steinberger, Peter, Kankainen, Matti, Aittokallio, Tero, Keränen, Mikko A. I., Korhonen, Matti, and Mustjoki, Satu

   Blood Feb 2020

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   In a study reported in this Plenary Paper, Dufva and colleagues used functional drug and CRISPR screens to uncover new biology about modulation of responses to

3. Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

   Dufva, Olli, Kankainen, Matti, Kelkka, Tiina, Sekiguchi, Nodoka, Awad, Shady Adnan, Eldfors, Samuli, Yadav, Bhagwan, Kuusanmäki, Heikki, Malani, Disha, Andersson, Emma I., Pietarinen, Paavo, Saikko, Leena, Kovanen, Panu E., Ojala, Teija, Lee, Dean A., Loughran, Thomas P., Nakazawa, Hideyuki, Suzumiya, Junji, Suzuki, Ritsuro, Ko, Young Hyeh, Kim, Won Seog, Chuang, Shih-Sung, Aittokallio, Tero, Chan, Wing C., Ohshima, Koichi, Ishida, Fumihiro, and Mustjoki, Satu

   Nature Communications Apr 2018

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   Aggressive natural killer-cell leukemia (ANKL) has few targeted therapies. Here ANKL patients are reported to harbor STAT3, RAS-MAPK pathway, DDX3X and epigenetic modifier mutations; and drug sensitivity profiling uncovers the importance of the JAK-STAT pathway, revealing potential ANKL therapeutic targets.

all publications

2021

1. Genome-scale screens identify factors regulating tumor cell responses to natural killer cells

   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.

   Nature Genetics Jul 2021

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   To systematically define molecular features in human tumor cells that determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly annotated ‘DNA-barcoded’ solid tumor cell lines in multiplexed format and applied genome-scale CRISPR-based gene-editing screens in several solid tumor cell lines, to functionally interrogate which genes in tumor cells regulate the response to NK cells. In these orthogonal studies, NK cell–sensitive tumor cells tend to exhibit ‘mesenchymal-like’ transcriptional programs; high transcriptional signature for chromatin remodeling complexes; high levels of B7-H6 (NCR3LG1); and low levels of HLA-E/antigen presentation genes. Importantly, transcriptional signatures of NK cell–sensitive tumor cells correlate with immune checkpoint inhibitor (ICI) resistance in clinical samples. This study provides a comprehensive map of mechanisms regulating tumor cell responses to NK cells, with implications for future biomarker-driven applications of NK cell immunotherapies.

2020

1. Immune profiles in acute myeloid leukemia bone marrow associate with patient age, T-cell receptor clonality, and survival

   Brück, Oscar, Dufva, Olli, Hohtari, Helena, Blom, Sami, Turkki, Riku, Ilander, Mette, Kovanen, Panu, Pallaud, Celine, Ramos, Pedro Marques, Lähteenmäki, Hanna, Välimäki, Katja, El Missiry, Mohamed, Ribeiro, Antonio, Kallioniemi, Olli, Porkka, Kimmo, Pellinen, Teijo, and Mustjoki, Satu

   Blood Advances Jan 2020

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   Abstract The immunologic microenvironment in various solid tumors is aberrant and correlates with clinical survival. Here, we present a comprehensive analysis of the immune environment of acute myeloid leukemia (AML) bone marrow (BM) at diagnosis. We compared the immunologic landscape of formalin-fixed paraffin-embedded BM trephine samples from AML (n = 69), chronic myeloid leukemia (CML; n = 56), and B-cell acute lymphoblastic leukemia (B-ALL) patients (n = 52) at diagnosis to controls (n = 12) with 30 immunophenotype markers using multiplex immunohistochemistry and computerized image analysis. We identified distinct immunologic profiles specific for leukemia subtypes and controls enabling accurate classification of AML (area under the curve [AUC] = 1.0), CML (AUC = 0.99), B-ALL (AUC = 0.96), and control subjects (AUC = 1.0). Interestingly, 2 major immunologic AML clusters differing in age, T-cell receptor clonality, and survival were discovered. A low proportion of regulatory T cells and pSTAT1+cMAF− monocytes were identified as novel biomarkers of superior event-free survival in intensively treated AML patients. Moreover, we demonstrated that AML BM and peripheral blood samples are dissimilar in terms of immune cell phenotypes. To conclude, our study shows that the immunologic landscape considerably varies by leukemia subtype suggesting disease-specific immunoregulation. Furthermore, the association of the AML immune microenvironment with clinical parameters suggests a rationale for including immunologic parameters to improve disease classification or even patient risk stratification.

2. Immunogenomic Landscape of Hematological Malignancies

   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

   Cancer Cell Jul 2020

   Abs HTML PDF

   Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-γ response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.

3. Integrated drug profiling and CRISPR screening identify essential pathways for CAR T-cell cytotoxicity

   Dufva, Olli, Koski, Jan, Maliniemi, Pilvi, Ianevski, Aleksandr, Klievink, Jay, Leitner, Judith, Pölönen, Petri, Hohtari, Helena, Saeed, Khalid, Hannunen, Tiina, Ellonen, Pekka, Steinberger, Peter, Kankainen, Matti, Aittokallio, Tero, Keränen, Mikko A. I., Korhonen, Matti, and Mustjoki, Satu

   Blood Feb 2020

   Abs HTML PDF

   In a study reported in this Plenary Paper, Dufva and colleagues used functional drug and CRISPR screens to uncover new biology about modulation of responses to

4. Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia

   Kuusanmäki, Heikki, Leppä, Aino-Maija, Pölönen, Petri, Kontro, Mika, Dufva, Olli, Deb, Debashish, Yadav, Bhagwan, Brück, Oscar, Kumar, Ashwini, Everaus, Hele, Gjertsen, Bjørn T., Heinäniemi, Merja, Porkka, Kimmo, Mustjoki, Satu, and Heckman, Caroline A.

   Haematologica Mar 2020
5. RUNX1 mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses

   Adnan Awad, Shady, Dufva, Olli, Ianevski, Aleksandr, Ghimire, Bishwa, Koski, Jan, Maliniemi, Pilvi, Thomson, Daniel, Schreiber, Andreas, Heckman, Caroline A., Koskenvesa, Perttu, Korhonen, Matti, Porkka, Kimmo, Branford, Susan, Aittokallio, Tero, Kankainen, Matti, and Mustjoki, Satu

   Leukemia Aug 2020

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   Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations, RUNX1 mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate that PHF6 and BCORL1 mutations, IKZF1 deletions, and AID/RAG-mediated rearrangements are enriched in RUNX1mut BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primary RUNX1mut CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity of RUNX1mut blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells from RUNX1mut patients to be highly responsive for mTOR-, BCL2-, and VEGFR inhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygous RUNX1−/− and heterozygous RUNX1−/mut BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role of RUNX1 mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treating RUNX1mut BP-CML patients.

6. Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis

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

   Blood Dec 2020

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   The KIT D816V mutation is found in more than 80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. KIT D816V therefore represents a prime therapeutic target for SM. Here we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM (ASM) and mast cell leukemia (MCL) to develop a patient-specific SM disease model for mechanistic and drug discovery studies. KIT D816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR/Cas9n-engineered KIT D816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed for KIT D816V iPSC hematopoiesis. KIT D816V causes constitutive activation of the KIT tyrosine kinase receptor and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib, an FDA approved angiokinase inhibitor that targets VEGFR, PDGFR and FGFR, as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derived KIT D816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the ATP binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V targeted therapy of advanced SM.

2019

1. Data-driven characterization of molecular phenotypes across heterogeneous sample collections

   Mehtonen, Juha, Pölönen, Petri, Häyrynen, Sergei, Dufva, Olli, Lin, Jake, Liuksiala, Thomas, Granberg, Kirsi, Lohi, Olli, Hautamäki, Ville, Nykter, Matti, and Heinäniemi, Merja

   Nucleic Acids Research Jul 2019

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   Abstract. Existing large gene expression data repositories hold enormous potential to elucidate disease mechanisms, characterize changes in cellular pathways,

2018

1. Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

   Dufva, Olli, Kankainen, Matti, Kelkka, Tiina, Sekiguchi, Nodoka, Awad, Shady Adnan, Eldfors, Samuli, Yadav, Bhagwan, Kuusanmäki, Heikki, Malani, Disha, Andersson, Emma I., Pietarinen, Paavo, Saikko, Leena, Kovanen, Panu E., Ojala, Teija, Lee, Dean A., Loughran, Thomas P., Nakazawa, Hideyuki, Suzumiya, Junji, Suzuki, Ritsuro, Ko, Young Hyeh, Kim, Won Seog, Chuang, Shih-Sung, Aittokallio, Tero, Chan, Wing C., Ohshima, Koichi, Ishida, Fumihiro, and Mustjoki, Satu

   Nature Communications Apr 2018

   Abs HTML PDF

   Aggressive natural killer-cell leukemia (ANKL) has few targeted therapies. Here ANKL patients are reported to harbor STAT3, RAS-MAPK pathway, DDX3X and epigenetic modifier mutations; and drug sensitivity profiling uncovers the importance of the JAK-STAT pathway, revealing potential ANKL therapeutic targets.

2. Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML

   Brück, Oscar, Blom, Sami, Dufva, Olli, Turkki, Riku, Chheda, Himanshu, Ribeiro, Antonio, Kovanen, Panu, Aittokallio, Tero, Koskenvesa, Perttu, Kallioniemi, Olli, Porkka, Kimmo, Pellinen, Teijo, and Mustjoki, Satu

   Leukemia Jul 2018

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   Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients’ CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+TIM3−CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.

3. Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling

   Andersson, E. I., Pützer, S., Yadav, B., Dufva, O., Khan, S., He, L., Sellner, L., Schrader, A., Crispatzu, G., Oleś, M., Zhang, H., Adnan-Awad, S., Lagström, S., Bellanger, D., Mpindi, J. P., Eldfors, S., Pemovska, T., Pietarinen, P., Lauhio, A., Tomska, K., Cuesta-Mateos, C., Faber, E., Koschmieder, S., Brümmendorf, T. H., Kytölä, S., Savolainen, E.-R., Siitonen, T., Ellonen, P., Kallioniemi, O., Wennerberg, K., Ding, W., Stern, M.-H., Huber, W., Anders, S., Tang, J., Aittokallio, T., Zenz, T., Herling, M., and Mustjoki, S.

   Leukemia 2018

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   T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is \textless2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

2017

1. Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling

   Kuusanmäki, Heikki, Dufva, Olli, Parri, Elina, Adrichem, Arjan J., Rajala, Hanna, Majumder, Muntasir M., Yadav, Bhagwan, Parsons, Alun, Chan, Wing C., Wennerberg, Krister, Mustjoki, Satu, and Heckman, Caroline A.

   Oncotarget Nov 2017

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   Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability. We identified JAK, mTOR, Hsp90 and CDK inhibitors as potent inhibitors of both WT and mutant STAT3 activity. The Hsp90 inhibitor luminespib was highly effective at reducing the viability of mutant STAT3 NK cell lines and LGL leukemia patient samples. Luminespib decreased the phosphorylation of mutant STAT3 at Y705, whereas JAK1/JAK2 inhibitor ruxolitinib had reduced efficacy on mutant STAT3 phosphorylation. Additionally, combinations involving Hsp90, JAK and mTOR inhibitors were more effective at reducing cell viability than single agents. Our findings show alternative approaches to inhibit STAT3 activity and suggest Hsp90 as a therapeutic target in lymphoproliferative disorders with constitutively active STAT3.

2. The SCLtTAxBCR-ABL transgenic mouse model closely reflects the differential effects of dasatinib on normal and malignant hematopoiesis in chronic phase-CML patients

   Schubert, Claudia, Chatain, Nicolas, Braunschweig, Till, Schemionek, Mirle, Feldberg, Kristina, Hoffmann, Melanie, Dufva, Olli, Mustjoki, Satu, Brümmendorf, Tim H., and Koschmieder, Steffen

   Oncotarget May 2017

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   The second generation tyrosine kinase inhibitor (TKI) dasatinib is a clinically approved drug for chronic myeloid leukemia (CML) as well as Ph+ acute lymphoblastic leukemia. In addition to its antileukemic effects, dasatinib was shown to impact on normal hematopoiesis and cells of the immune system.Due to the fact that the murine in vivo studies so far have not been performed in a chronic-phase CML model under steady-state conditions, our aim was to study the hematopoietic effects of dasatinib (20 mg/kg p.o.) in BCR-ABL expressing SCLtTAxBCR-ABL double transgenic (dtg) mice. Dasatinib robustly antagonized the CML phenotype in vivo in our transgenic mouse model, and this effect included both mature and immature cell populations. However, similar to patients with CML, the fraction of LinnegSca-1+KIT+CD48negCD150+ hematopoietic stem cells was not reduced by dasatinib treatment, suggesting that these cells are not oncogene-addicted. Moreover, we observed differential effects of dasatinib in these animals as compared to wild-type (wt) animals: while granulocytes were significantly reduced in dtg animals, they were increased in wt mice. And Ter119+ erythrocytic and B220+ B cells were increased in dtg mice but decreased in wt mice. Finally, while dasatinib induced a shift from CD49b/NK1.1 positive NK cells from the bone marrow to the spleen in wt animals, there was no change in dtg mice. In conclusion, the present mouse model provides a useful tool to study mechanisms of TKI resistance and dasatinib-associated beneficial effects and adverse events.

2016

1. T cells and cancer - why do the killers become exhausted?

   Brück, Oscar, Keränen, Mikko, Dufva, Olli, Kreutzman, Anna, and Mustjoki, Satu

   Duodecim; Laaketieteellinen Aikakauskirja 2016

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   Nascent tumors are mostly eliminated by the immune system. During carcinogenesis mutated cells find a way to escape from the immune system´s surveillance. As the tumor microenvironment evolves it becomes increasingly difficult for T cells to recognize and kill cancer cells. Recently, novel immunological targets have been recognized and potent immunomodulatory drugs discovered in clinical trials. This has resulted in the emergence of immunotherapy as a novel potent therapy for cancer in addition to chemotherapy, targeted therapy, operative therapy and radiotherapy.

2015

1. Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia

   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., Chapelle, Albert, and Vahteristo, Pia

   Oncotarget Jan 2015

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   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.

2014

1. Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance

   Wiener, Zoltán, Högström, Jenny, Hyvönen, Ville, Band, Arja M., Kallio, Pauliina, Holopainen, Tanja, Dufva, Olli, Haglund, Caj, Kruuna, Olli, Oliver, Guillermo, Ben-Neriah, Yinon, and Alitalo, Kari

   Cell Reports Sep 2014

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   Colorectal cancer (CRC) initiation and growth is often attributed to stem cells, yet little is known about the regulation of these cells. We show here that a subpopulation of Prox1-transcription-factor-expressing cells have stem cell activity in intestinal adenomas, but not in the normal intestine. Using in vivo models and 3D ex vivo organoid cultures of mouse adenomas and human CRC, we found that Prox1 deletion reduced the number of stem cells and cell proliferation and decreased intestinal tumor growth via induction of annexin A1 and reduction of the actin-binding protein filamin A, which has been implicated as a prognostic marker in CRC. Loss of Prox1 also decreased autophagy and the survival of hypoxic tumor cells in tumor transplants. Thus, Prox1 is essential for the expansion of the stem cell pool in intestinal adenomas and CRC without being critical for the normal functions of the gut.