Olli Dufva
University of Helsinki
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Publication
Featured researches published by Olli Dufva.
Cell Reports | 2014
Zoltán Wiener; Jenny Högström; Ville Hyvönen; Arja M. Band; Pauliina Kallio; Tanja Holopainen; Olli Dufva; Caj Haglund; Olli Kruuna; Guillermo Oliver; Yinon Ben-Neriah; Kari Alitalo
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.
Leukemia | 2018
Emma I. Andersson; S. Pützer; Bhagwan Yadav; Olli Dufva; Sofia Khan; Liye He; Leopold Sellner; A Schrader; G Crispatzu; M Ole sacute; Henan Zhang; S Adnan; Sonja Lagström; D Bellanger; John-Patrick Mpindi; Samuli Eldfors; Tea Pemovska; Paavo Pietarinen; Anneli Lauhio; K Tomska; Carlos Cuesta-Mateos; Edgar Faber; Steffen Koschmieder; Tim H. Brümmendorf; Soili Kytölä; E-R Savolainen; T Siitonen; Pekka Ellonen; Olli-P. Kallioniemi; Krister Wennerberg
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 <2 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.
Nature Communications | 2018
Olli Dufva; Matti Kankainen; Tiina Kelkka; Nodoka Sekiguchi; Shady Adnan Awad; Samuli Eldfors; Bhagwan Yadav; Heikki Kuusanmäki; Disha Malani; Emma I. Andersson; Paavo Pietarinen; Leena Saikko; Panu E. Kovanen; Teija Ojala; Dean A. Lee; Thomas P. Loughran; Hideyuki Nakazawa; Junji Suzumiya; Ritsuro Suzuki; Young Hyeh Ko; Won Seog Kim; Shih-Sung Chuang; Tero Aittokallio; Wing C. Chan; Koichi Ohshima; Fumihiro Ishida; Satu Mustjoki
Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.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.
Oncotarget | 2017
Heikki Kuusanmäki; Olli Dufva; Elina Parri; Arjan J. van Adrichem; Hanna Rajala; Muntasir Mamun Majumder; Bhagwan Yadav; Alun Parsons; Wing C. Chan; Krister Wennerberg; Satu Mustjoki; Caroline Heckman
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.
Oncotarget | 2017
Claudia Schubert; Nicolas Chatain; Till Braunschweig; Mirle Schemionek; Kristina Feldberg; Melanie Hoffmann; Olli Dufva; Satu Mustjoki; Tim H. Brümmendorf; Steffen Koschmieder
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.
Cancer immunology research | 2016
Olli Dufva; Tiina Kasanen; Mohamed El Missiry; Judith Klievink; Hanna Lähteenmäki; Satu Mustjoki
The potential of immune checkpoint inhibition in many hematological malignancies such as chronic myeloid leukemia (CML) has not been characterized in detail. CML is a hematopoietic stem cell disease driven by the BCR-ABL fusion gene. Tyrosine kinase inhibitor (TKI) therapy is able to induce remissions in the majority of patients. Despite treatment responses, leukemic stem cells persist in the bone marrow (BM). Enhancing antitumor immune responses has been suggested as a potential strategy of enabling treatment discontinuation and disease control in CML. We hypothesized that the bone marrow may represent a distinct immunological milieu in CML patients. Furthermore, TKI therapy has been shown to induce immunological changes. Therefore, we evaluated the expression of immune checkpoint molecules in paired samples from BM and peripheral blood (PB) in chronic phase CML patients at diagnosis and during treatment with TKIs. In addition, we monitored changes in the BM T cell receptor (TCR) repertoire induced by TKI therapy and disease resolution. We performed multicolor flow cytometry on frozen PB and BM samples from chronic phase CML patients at diagnosis and during treatment with the tyrosine kinase inhibitors imatinib, dasatinib and nilotinib as well as healthy controls. We analyzed the expression of PD-1, CTLA-4, LAG-3, ICOS and TIM-3 on T cells and PD-L1, PD-L2, CD80 and CD86 on antigen-presenting cells and CD34+ leukemic progenitor cells. TCR repertoire was assayed by deep sequencing of the CDR3 region using the immunoSEQ assay. At diagnosis, CD8+ T cells in the bone marrow exhibited a more exhausted phenotype compared to peripheral blood as measured by PD-1 positivity (26.1 vs. 12.7%, p = 0.001). This difference was recapitulated in all T cell subsets, including effector memory (TEM), terminally differentiated (TEMRA), central memory (TCM) and naive, with the highest PD-1 positivity in TEM and TEMRA cells. In addition, dendritic cells as well as leukemic CD34+ progenitor cells expressed higher levels of PD-L1 and CD86 in BM compared to PB at diagnosis. Interestingly, TKI therapy led to a reduction of PD-1-positive CD8+ T cells in the BM after 1 and 6 months of treatment. This was accompanied by a concomitant decrease in PD-L1 and CD86 positivity on dendritic cells. Finally, treatment with dasatinib led to a reduction in TCR repertoire diversity and increased clonality at 6 months, whereas imatinib or nilotinib did not alter the repertoire diversity. In conclusion, BM and PB seem to exhibit different immunological milieus in terms of expression of immune checkpoint molecules in CML. During TKI therapy both PD-1 and PD-L1 levels decrease, suggesting at least partial reversal of immune cell exhaustion. Treatment with the TKI dasatinib is able to drive the TCR repertoire towards a more clonal composition, which has been associated with good responses to checkpoint blockade. Thus, targeted therapies such as TKIs are able to modulate immune checkpoints and T cell activity in unexpected ways, providing a potential strategy for enhancing immunotherapies in combination treatment regimens. Citation Format: Olli Dufva, Tiina Kasanen, Mohamed El Missiry, Judith Klievink, Hanna Lahteenmaki, Satu Mustjoki. Tyrosine kinase inhibitor therapy modulates immune checkpoints and TCR repertoire diversity in chronic myeloid leukemia [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A115.
Cancer Research | 2014
Zoltán Wiener; Ville Hyvönen; Jenny Högström; Tanja Holopainen; Arja M. Band; Pauliina Kallio; Olli Dufva; Caj Haglund; Olli Kruuna; Guillermo Oliver; Yinon Ben-Neriah; Kari Alitalo
Colorectal cancer (CRC) is one of the leading causes of cancer mortality in the Western countries. In most of the CRC patients, an initial mutation occurs in the APC or CTNNB1 genes, leading to the ligand-independent activation of the canonical Wnt pathway. Besides having a central role in the development of CRC, the Wnt pathway plays a critical role also in the maintenance of the normal intestine. Attempts at therapeutic inhibition of this pathway could thus lead to serious side effects in CRC patients. We have previously shown that the Prox1 transcription factor is induced in the intestinal epithelium by mutations activating the Wnt pathway and it critically contributes to CRC progression via an unknown mechanism. Here we provide evidence that Prox1 expression is induced in the Lgr5+ adenoma stem cells early after Apc deletion. Our in vivo models and ex vivo organoid experiments suggest that Prox1 silencing or deletion restricts the expansion of the Lgr5+ adenoma stem cell population both in humans and in mice. Interestingly, silencing the phospholipid binding protein Annexin A1 (Anxa1), a gene suppressed by Prox1, is responsible for several of the effects of Prox1 on adenoma cells, such as the re-organization of the actin cytoskeleton, enhanced stem cell activity and tumor growth. Furthermore, Prox1 deletion abnormally increases the mTORC1 pathway activity, which results in decreased survival of the adenoma stem cells. Since Prox1 is expressed at low level only in rare neuroendocrine cells and in some Paneth cells in the wild type intestinal epithelium, furthermore, its genetic deletion in the adult gut does not lead to obvious phenotypes, Prox1 may serve as an attractive therapeutic target for restricting the progression of early intestinal adenomas. Citation Format: Zoltan Wiener, Ville Hyvonen, Jenny Hogstrom, Tanja Holopainen, Arja Band, Pauliina Kallio, Olli Dufva, Caj Haglund, Olli Kruuna, Guillermo Oliver, Yinon Ben-Neriah, Kari Alitalo. The Wnt-target Prox1 promotes colorectal cancer stem cell survival to fuel tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1908. doi:10.1158/1538-7445.AM2014-1908
Oncotarget | 2015
Kati Kämpjärvi; Tiina M. Jarvinen; Tuomas Heikkinen; Amy S. Ruppert; Leigha Senter; Kevin W. Hoag; Olli Dufva; Mika Kontro; Laura Z. Rassenti; Erin Hertlein; Thomas J. Kipps; Kimmo Porkka; John C. Byrd; Albert de la Chapelle; Pia Vahteristo
Archive | 2018
Mikko A.I. Keränen; Olli Dufva; Samu Kurki
Leukemia | 2018
Oscar Brück; Sami Blom; Olli Dufva; Riku Turkki; Himanshu Chheda; Antonio Ribeiro; Panu E. Kovanen; Tero Aittokallio; Perttu Koskenvesa; Olli Kallioniemi; Kimmo Porkka; Teijo Pellinen; Satu Mustjoki