eRapport

Stem Cell Aging and Cancer

Prosjekt
Prosjektnummer
Strategisk-HN06-14
Ansvarlig person
Lorena Aranz Salas
Institusjon
UiT Norges arktiske universitet
Prosjektkategori
Miljøstøtte
Helsekategori
Blood, Cancer and neoplasms, Inflammatory and immune system
Forskningsaktivitet
2. Aetiology, 5. Treatment Development
Rapporter
2024 - sluttrapport
Our group aims at understanding the mechanisms of hematopoietic stem cell (HSC) malignant transformation and the role of the microenvironment, with a focus on the cellular components, inflammation and signaling oncometabolites. Our goal is the identification of novel therapeutic targets for acute myeloid leukaemia (AML) and other blood cancers. In December 2023, the team leader Lorena Arranz and her team resigned the positions at UiT - The Arctic University of Norway and moved to the University of Oslo for the establishment of our newly awarded Centre of Excellence on Embryology and Healthy Development (CRESCO) funded from the Research Council of Norway (NFR), where we continue to work on our mission. Dr. Arranz is the current Deputy Director and will be Centre Director during the second 5-year period. Despite extensive delays, related mainly to lack of adequate equipment and facilities for several years after the start of the position at UiT in Nov 2014 and later close down of the animal facility for four years, our team was able to overcome these challenges, gaining national and international visibility within our field. The work from this grant resulted in numerous projects and collaborations still ongoing, and the grant will be acknowledged upon their publication. We would like to highlight our results on three major research lines: 1) We have found that bone marrow neuropathy is a common event in hematopoietic malignancies not restricted to myeloid malignancies that involves profound degradation of sympathetic fibres and contributes to disease. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the bone marrow and is the first line treatment for AML, acute lymphoblastic leukemia and other blood cancer patients. The work is currently under Revision in Experimental Hematology and Oncology, and expected to be published in early 2025. This project received additional funding from NFR, Helse Nord, the Norwegian Cancer Society and the Aakre-Stiftelsen Foundation. The current follow-up of this project is funded from NFR and CRESCO. 2) Within the same funding above, we explored the role of interleukin-1β (IL-1β) repressor cytokine, IL-1 receptor antagonist (IL-1rn), in healthy and abnormal hematopoiesis. Our data revealed that HSC differentiation is controlled by balanced IL-1β/IL-1rn levels under steady-state, and that loss of repression of IL-1β signaling may underlie pre-leukemic lesion and AML progression. We depicted a potential origin for high IL-1β in human AML, and a type of patient that may be particularly good responder to anti-IL-1β therapies over patients that present with high IL-1β resulting from lesions downstream of the receptor (Villatoro et al, Nature Communications 2023). Dr. Arranz was invited to present this work in numerous national and international venues, including the prestigious EHA2021 Molecular Hematology Workshop. The follow-up work is funded by NFR and CRESCO. 3) We have shown that the oncometabolite succinate, signaling through its receptor (Sucnr1), in fact estricts hematopoiesis at least partially through the multipotent progenitors and via a previously unnoticed pathway. Its dysregulation emerges as contributor to hematopoietic malignancy that may open new therapeutic avenues. This work is currently under Revision in Nature Communications, and expected to be published in mid-2025. This project received additional funding from NFR and CRESCO. Dr. Arranz was invited to present this work in numerous venues, including the prestigious YoungEHA Research Meeting in EHA2018. Dr. Cuminetti, the first author, has presented the work as oral communication (EHA2022) and posters (EHA Research Conference 2024, Updates on Genetics and Epigenetics of Haematological Malignancies: From Knowledge to Applications, Josep Carreras Leukaemia Research Institute 2024) and received a Molecular Oncology Poster Award. The follow-up work has received funding from EHA. The mid- and long-term impact on health services derived from the results of this grant relate mainly to the following: 1) As a follow up of our work on bone marrow neuropathy in hematopoietic malignancies, we are currently working on a project funded from NFR where together with our collaborators F. Ferrer-Marin and R. Teruel-Montoya (University Hospital JM Morales-Meseguer, Murcia, Spain), we have identified germinal loss of function variants in NTRK1 that encodes for Tropomyosin receptor kinase A (TRKA), also known as high affinity nerve growth factor (NGF) receptor, which are present in family members with mutually exclusive driver mutations for myeloproliferative neoplasms (MPN). We are currently characterising the pathogenic potential of these variants in both the bone marrow hematopoietic and stromal compartments in vivo using gene knock-out, in presence or absence of driver mutations. We are also using human hematopoietic progenitors from healthy donoros in serial xenografts in vivo to evaluate the potential of these germline genetic variants to predispose to acquisition of somatic mutations at the single-cell level and the development of MPN. In the future, these data will serve to understand potentially important underlying factors contributing to differences in disease susceptibility and progression, as well as to guide future targeted personalized therapies for a subset of patients carriers of these variants. 2) As a next step of our work on IL-1 receptor antagonist (IL-1RN), we are currently planning a future Clinical Trial. The outcome of this research has pinpointed two drugs that may be beneficial for AML patients. These drugs are FDA-approved, and used relatively safely in unrelated diseases. We are currently applying for funding for a Clinical Trial that will be a Multicenter, open-label, single arm, phase II exploratory study to evaluate the use of IL-1RN (anakinra) as co-adjuvant or in monotherapy in a subset of patients with myeloid malignancies and presence of primary lesions in the IL1RN gene. We are planning the Clinical Trial as a national effort, with international collaborations within the European Hematology Association environment. As of today, we will do this together with H. Hjorth-Hansen (St Olavs Hospital, Trondheim), A. Vik (University Hospital of North Norway, Tromsø), B.T. Gjertsen (Haukeland University Hospital) and A. Lenartova (Department of Hematology at Oslo University Hospital) within Norway. A Spanish node is included as international collaborators so far and led by F. Ferrer (Hospital Universitario Morales-Meseguer, Murcia). Further, the FDA-approved drugs mentioned have certain limitations. Importantly, the CANTOS trial raised safety concerns due to higher incidence of deaths related to fatal infection in the Canakinumab treated versus the placebo group. Anakinra provides the potential advantage of opportunity to discontinue treatment fast in case of infection due to its short half-life of 4-6 hours. It is our aim to continue this project as an innovation project aimed towards prolonging the half-life of anakinra to some extent, to prevent burden of daily injections whilst improving both efficacy of treatment and quality of life of the patients. 3) In an increasingly obese and aged population, in the follow-up of our work on succinate and sucnr1, we will explore the role of the diet in the pro-leukemic adipocityc stem cell niche in the bone marrow and possibilities for therapeutic targeting.

During the project, the interaction with A. Vik as user representative has been dynamic. He has been instrumental in the implementation and development of the patient studies. Our communication has been frequent through various channels, providing him with regular opportunities to influence, develop and make suggestions for changes in aspects related to patients and hematologists. His perspective has been invaluable throughout the project. He has also been responsible for communication with patients, informing about the project to participate donating samples for research under our on-going REK. Within the framework of our ongoing research on IL-1 receptor antagonist, we will soon organize meetings including A. Vik, A. Lenartova, B.T. Gjertsen and other clinicians from the national and international arena, and involving user representatives from Blodkreftforeningen and the Patient Advocacy Committee from the European Hematology Association (EHA), to 1) Take part in Committees where this work, the current follow-up aimed at depicting the patients with best chances for success with the treatment that we have identified in this work and main results will be discussed. All members of the Committee will provide comments/suggestions based on their AML experiences, and these will be considered for implementation in the current follow-up of the Project, and 2) Discussion of the Clinical Trial that will be developed as a national effort, with international collaborations within EHA.

2023
Our group aims at understanding the molecular mechanisms of hematopoietic stem cell (HSC) malignant transformation and the role of the microenvironment where these cells reside, with a focus on inflammation and signaling oncometabolites. Our goal is the identification of novel therapeutic targets for acute myeloid leukaemia (AML) patients.AML is the most common form of acute leukaemia in adults. Its incidence increases with age and the prognosis for the older patient remains bleak. Overcoming these problems will require a better understanding of AML. During 2023, the grant has been mainly used to support and make progress on two projects, and we plan to submit and publish the associated manuscripts in 2024. Cancer and normal cells differ in their metabolism that is their way of obtaining energy. Alterations in steps of metabolic pathways link to cancer and resistance to therapies. Surrounding or distal normal cells can sense metabolic disturbances in cancer cells through sensing of metabolic intermediates, usually present inside the cell but released outside under particular conditions such as metabolic stress. These pathways have received little attention in the context of leukaemia. The metabolic intermediate succinate and its receptor (Sucnr1) have been scarcely explored in the context of hematopoiesis to date. Here, we show that low SUCNR1 represents a marker for reduced survival in AML patients. Treatments with succinate promoted disease progression in mouse models of pre-leukaemic myelopoiesis and AML, as well as in AML xenografts. In vivo global deletion of Sucnr1 induced expansion of haematopoietic stem and progenitor cells (HSPC) and haematopoiesis. Independent deletion of Sucnr1 from the haematopoietic system resulted in expansion of multipotent progenitors and differentiated cells, while deletion of Sucnr1 from stromal cells promoted expansion of stem cells. Our data reveal that Sucnr1 preserves transcriptional programs characteristic of HSPC via control of a novel pathway. Together, Sucnr1 signaling is a key regulatory pathway in the haematopoietic system that involves both the haematopoietic and stromal compartments of the bone marrow, and its dysregulation contributes to haematopoietic malignancies. This project provides insights into the basic processes that regulate blood stem cell function/dysfunction and knowledge of markers for patient prognosis. The therapeutic potential of these findings will be further explored in the future. V. Cuminetti presented this work at UiT and at CRESCO kick-off. Neuropathy of the bone marrow is essential for disease development in experimental models of JAK2-V617F+ myeloproliferative neoplasms (MPN) and MLL-AF9+ AML, and it is present in the bone marrow of human MPN patients. We show that neuropathy emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis and lymphoma/lymphoblastic leukemia, as well as in AML patients, and it involves severe ultrastructural damage. When further reinforced chemically, neuropathy promotes malignancy. Together, bone marrow neuropathy is a common event in hematopoietic malignancies that involves profound degradation of sympathetic fibres and contributes to disease. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the bone marrow and is the first line treatment for AML and acute lymphoblastic leukemia patients. M. Ferre discussed this project at the Experimental Health Research Conference (EHRC) - Mímisbrunnr 2023. During this year, the group leader was invited as speaker at the virtual seminar series "Cell Biology Scandinavia". She served as Referee for prestigiuos journals like EMBO Journal. Our work was featured in several Norwegian media. Dr. Arranz was promoted to Research Professor in May.

The interaction with Anders Vik, as user representative has been very dynamic during the whole duration of the project. He has been instrumental in the implementation and development of the patient studies. Patients have been informed about the project to participate donating samples for research under our on-going REK. We will in the future, as a next step of our current work on IL-1 receptor antagonist, organize meetings including A. Vik, B.T. Gjertsen and other clinicians from the national arena, and involving patients, user representatives and next of kin, in 1) Taking part in Committees where this work, the current follow-up aimed at depicting the patients with best chances for success with the treatment that we have developed in this work and main results will be discussed. All members of the Committee will provide comments/suggestions based on their AML experiences, and these will be considered for implementation in the current follow-up of the Project, and 2) in the Planning of a future Clinical Trial. The outcome of this research has pinpointed two drugs that may be beneficial for AML patients. These drugs are FDA-approved, and used safely in unrelated diseases. This means that in the near future, we will be able to apply for a Phase II/III Clinical Trial. We are planning to do this as a national effort, with international collaborations within the European Hematology Association environment.

2022
Our group aims at understanding the molecular mechanisms of hematopoietic stem cell (HSC) malignant transformation and the role of the microenvironment where these cells reside, with a focus on inflammation and signaling oncometabolites. Our goal is the identification of novel therapeutic targets for acute myeloid leukaemia (AML) patients.AML is characterized by expansion of abnormal myeloid blasts in the bone marrow, which derives in anemia, thrombocytopenia and infections. Intensive treatment with curative potential requires hospitalization during several months with potential for life-threatening risks, such as opportunistic infections. Only one-third of the patients are eligible for stem cell transplantation. Improving treatment strategies will require understanding the pathogenic mechanisms for AML development, and its clinical challenges. Our research aims at providing with knowledge of AML driving causes, and applying this knowledge in search of markers for patient diagnosis/prognosis, novel therapies, and treatment stratification of patients. During last year, A. Villatoro defended her PhD Thesis and we published part of our main project in Nature Communications. In the published manuscript, we explored the role of interleukin-1β (IL-1β) repressor cytokine, IL-1 receptor antagonist (IL-1rn), in both healthy and abnormal hematopoiesis. Low IL-1RN is frequent in AML patients and represents a prognostic marker of reduced survival. Treatments with IL-1RN and the IL-1β monoclonal antibody canakinumab reduce the expansion of leukemic cells, including CD34+ progenitors, in AML xenografts. In vivo deletion of IL-1rn induces hematopoietic stem cell (HSC) differentiation into the myeloid lineage and hampers B cell development via transcriptional activation of myeloid differentiation pathways dependent on NFκB. Low IL-1rn is present in an experimental model of pre-leukemic myelopoiesis, and IL-1rn deletion promotes myeloproliferation, which relies on the bone marrow hematopoietic and stromal compartments. Conversely, IL-1rn protects against pre-leukemic myelopoiesis. Our data reveal that HSC differentiation is controlled by balanced IL-1β/IL-1rn levels under steady-state, and that loss of repression of IL-1β signaling may underlie pre-leukemic lesion and AML progression (Villatoro et al, 2023). In addition, a collaborative study with the group of P Garcia at the University of Birmingham was also published in eLife. By using a combination of human AML cell lines and AML patient samples together with mouse stromal cells and a MLL-AF9 mouse model, we identified a novel crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption to feed the tricarboxylic acid cycle and lipid biosynthesis. We also found that acetate in stromal cells is derived from pyruvate via chemical conversion under the influence of reactive oxygen species (ROS) following ROS transfer from AML to stromal cells via gap junctions. Overall, we presented a unique metabolic communication between AML and stromal cells and propose two different molecular targets, ACSS2 and gap junctions, that could potentially be exploited for adjuvant therapy (Villaplana-Lopera et al, 2022). During 2022, the group leader was invited as speaker at NCMM (UiO) and The 57th NBS Contact Meeting. She continued to be approached to peer review projects for national institutions like Akershus universitetssykehus. She served as Abstract Referee for the European Hematology Association (EHA2022) and as Congress Chair in the Session “Biology of leukemic transformation” (EHA2022). V. Cuminetti was selected as speaker and presented novel data on another major project from the lab in the same session. Our work was also featured in several Norwegian and Spanish media.

The interaction with Anders Vik, as user representative has been very dynamic during the whole duration of the project. Patients have been informed about the project to participate donating samples for research under our on-going REK. Unfortunately, there has been no substantial additional patient participation, given the difficult logistics that we have faced to perform research with the animal facility closed down for almost four years, continuous delays in its reopening date with subsequent uncertainty for our group members, the group split in two different locations with constant travels and complex coordination among group members, and a pandemic during 2020. The animal facility reopened recently, and we closed down in Oslo and moved to Tromsø in Sept 2021 and resumed activity progressively. We are currently planning to organize meetings including A. Vik and involving patients in 1) Taking part in Committees where one of our Projects, its aims and main results will be discussed. All members of the Committee will provide comments/suggestions based on their AML experiences, and these will be considered for implementation in the current follow-up of the Project, and 2) Planning future Clinical Trial. The outcome of the that research has pinpointed two drugs that may be beneficial for AML patients. These drugs are FDA-approved, and used safely in unrelated diseases. This means that in the future, we will be able to apply for a Phase II/III Clinical Trial.

2021
Our group aims at understanding the molecular mechanisms of hematopoietic stem cell (HSC) malignant transformation and the role of the microenvironment where these cells reside, with a focus on inflammation and signaling oncometabolites. Our goal is the identification of novel therapeutic targets for acute myeloid leukaemia (AML) patients.AML is characterized by expansion of abnormal myeloid blasts in the bone marrow, which derives in anemia, thrombocytopenia and infections. Intensive treatment with curative potential requires hospitalization during several months with potential for life-threatening risks, such as opportunistic infections. Only one-third of the patients are eligible for stem cell transplantation. Improving treatment strategies will require understanding the pathogenic mechanisms for AML development, and its clinical challenges. Our research aims at providing with knowledge of AML driving causes, and applying this knowledge in search of markers for patient diagnosis/prognosis, novel therapies, and treatment stratification of patients. During last year, we have confirmed and strengthen several relevant aspects of the work in the project focussed on the requirement for specific proinflammatory signals to mediate the interaction of the mutant hematopoietic stem cell with its niche. In addition to IL-1beta, IL-1R1 and the cytokine that counteracts the function of IL-1beta, we have analyzed additional components of the pathway including IL-1 receptor accessory protein, needed to signal through IL-1R1, in both mice and patients with myeloid leukemia as well as in mice deleted for the cytokine that controls IL-1beta function. In the latter, we have studied the potential in vivo role of IL-1alpha as well as the relevant cellular components producing IL-1beta and its counteracting cytokine at the individual level, through both imaging the expression of the cytokines with RNA fluorescence in situ hybridization as well as single-cell RNA-sequencing. Some of the main results obtained in the Mx1-Cre NRAS-G12D model have been reproduced with a different model of NRAS-G12D, i.e. Vav-Cre NRAS-G12D that is selective to the hematopoietic system and constitutive. Hence, it prevents any potential confounding effects derived from the inducing agent. We have studied the nuclear translocation of the p50/p65 NFκB heterodimer. The results have confirmed increased NF-kB translocation in CD34+ progenitors from AML patients versus healthy donors, which complements our previous result showing increased phosphorylation of p65 NF-kB as a readout for activation. Finally, we have reinforced several parts of the bioinformatic work including the predictive value of IL-1beta counteracting cytokine, NF-kB activation as evidenced by target gene expression in all mouse models and comparisons of our data with previously published datasets using direct overactivation of IL-1beta. Thus, our data support that targeting the unbalanced anti-inflammation may be clinically relevant for AML patients, and it is our purpose to develop a clinical trial in the future where the AML patients with best chances to benefit for this treatment are adequately selected based on disease molecular features. The results are currently awaiting resubmission in a highly ranked scientific journal. Due to further delays related to AKM closure, A. Villatoro will defend her PhD Thesis during 2022. During 2021, the group leader was invited as speaker at UiO, EHA2021, Akershus and the NCMM. She continued to be approached to peer review projects for prestigious international funding bodies like the Medical Research Council UK as well as national institutions like Akershus universitetssykehus. Håkon Olsen and Benjamin Hellsten performed and defended his BSc Thesis, on several aspects of succinate biology in the bone marrow.

The interaction with Dr. Anders Vik, as user representative, has been very dynamic during the whole duration of the project. Unfortunately, there has been no substantial patient participation so far, given the difficult logistics that we are facing to perform research with the animal facility closed down for almost four years, continuous delays in its reopening date with subsequent uncertainty for our group members, the group split in two different locations with constant travels and complex coordination, a pandemic during 2020-2021 and return to Tromsø in 2021. The animal facility reopened recently, and we moved from Oslo in Sept 2021, allowed to resume activity in Tromsø slowly. From now we will have availability to organize meetings including A. Vik and involving patients in 1) Taking part in Committees where the Project, its aims and main results will be discussed. All members of the Committee will provide comments/suggestions based on their AML experiences, and these will be considered for implementation for the future in the follow-up of the Project, and 2) Planning future Clinical Trial. The outcome of the present research has pinpointed two drugs that may be beneficial for AML patients. These drugs are FDA-approved, and used safely in unrelated diseases. This means that in the future, we will be able to apply for a Phase II/III Clinical Trial. Up to date, patients have been informed about the project to participate donating samples for research under our on-going REK.

2020
Our group aims at understanding the molecular mechanisms of hematopoietic stem cell (HSC) malignant transformation and the role of the microenvironment where these cells reside, with a focus on inflammation and signaling oncometabolites. Our goal is the identification of novel therapeutic targets for acute myeloid leukaemia (AML) patients.AML is characterized by expansion of abnormal white blood cells, myeloid blasts, in the bone marrow, which secondarily derives in anemia, thrombocytopenia and infections. Intensive treatment with curative potential requires hospitalization during several months with potential for life-threatening risks, such as opportunistic infections. Only one-third of the patients are eligible for stem cell transplantation. Improving treatment strategies will require understanding the pathogenic mechanisms for AML development, and its clinical challenges. Our research aims at providing with knowledge of AML driving causes, and applying this knowledge in search of markers for patient diagnosis/prognosis, novel therapies, and treatment stratification of patients. During last year, we have continued to make advances in the project focussed on the requirement for specific proinflammatory signals to mediate the interaction of the mutant hematopoietic stem cell (HSC) with its niche. These data are currently in revision 1 in a highly regarded international scientific journal. Due to further delays related to AKM closure, A. Villatoro will defend her PhD Thesis during 2021. In this work, we have demonstrated that defects in anti-inflammatory mechanisms that control inflammation lead to differentiation bias of HSC into the myeloid lineage in otherwise healthy mice. Unbalanced anti-inflammatory mechanisms are present in mouse models with aberrant RAS and in a cohort of AML patients, and lead to aggravation of disease progression in mouse models. Unbalanced anti-inflammatory pathway is particularly low in those patients with lower maturation/differentiation profiles according to the French-American-British classification of AML, and is a prognostic marker of reduced survival for AML patients, in our cohort and in an independent bigger cohort. We have used the anti-inflammatory defects as therapeutic targets in the NRAS-G12D+ mouse model of aberrant myelopoiesis. Xenografts of leukemic HSC derived from patients and transplanted into immunodeficient humanized mice as a preclinical model showed promising therapeutic value of this drug, similar to an additional blocking strategy of the same pathway currently in a Phase II clinical trial for the treatment of low or intermediate risk MDS and CML. Thus, our data support that targeting the unbalanced anti-inflammation may be clinically relevant for AML patients. We aim at developing a clinical trial in the future where the AML patients most likely to benefit for this treatment are adequately selected based on disease molecular features. During 2020, the group leader was invited as speaker to the 6th Annual Meeting Bergen Stem Cell Consortium, Solstrand (20.10.2020), and participated as lecturer at the NCMM Molecular Medicine Research Course for PhD students (MF9120BTS; 11.2020). She concluded the first AURORA Outstanding Program at UiT http://staten.wpengine.com/ (2018-2020). Listen to her participation at Investigadores por el Mundo here: https://www.investigadoresporelmundo.com/podcast/celulas-madre-en-neoplasias-hematopoyeticas-publicaciones-cientificas-ref100078530.html (in Spanish). She continued to be approached to peer review projects for prestigious international funding bodies like the Medical Research Council UK and Blood Cancer UK as well as national institutions like Akershus universitetssykehus. Gabriel Dahlquist performed and defended his BSc Thesis, Succinate receptor 1 presence in the bone marrow.

The interaction with Dr. Anders Vik, as user representative, has been very dynamic during the whole duration of the project. Unfortunately, there has been no substantial patient participation so far, given the difficult logistics that we are facing to perform research with the animal facility closed down for almost four years, continuous delays in its reopening date with subsequent uncertainty for our group members, the group split in two different locations with constant travels and complex coordination among group members, and a pandemic during 2020. The animal facility reopened recently, and we are planning to close down in Oslo and move to Tromsø progressively, which will facilitate our availability to organize meetings including Anders Vik and involving patients in 1) Taking part in Committees where the Project, its aims and main results will be discussed. All members of the Committee will provide comments/suggestions based on their AML experiences, and these will be considered for implementation for the future in the follow-up of the Project, and 2) Planning future Clinical Trial. The outcome of the present research has pinpointed two drugs that may be beneficial for AML patients. These drugs are FDA-approved, and used safely in unrelated diseases. This means that in the future, we will be able to apply for a Phase II/III Clinical Trial. Up to date, patients have been informed about the project to participate donating samples for research under our on-going REK.

2019
Our group aims at understanding the molecular mechanisms of hematopoietic stem cell (HSC) malignant transformation and the role of the microenvironment where these cells reside, with a focus on inflammation and signaling oncometabolites. Our goal is the identification of novel therapeutic targets for acute myeloid leukaemia (AML) patients.AML is characterized by expansion of abnormal white blood cells, myeloid blasts, in the bone marrow, which secondarily derives in anemia, thrombocytopenia and infections. Intensive treatment with curative potential requires hospitalization during several months with potential for life-threatening risks, such as opportunistic infections. Only about one-third of the patients are eligible for stem cell transplantation. Improving treatment strategies will require understanding the pathogenic mechanisms for AML development, and its clinical complications and challenges. Our research aims at providing with knowledge of AML driving causes, and applying this knowledge in search of markers for patient diagnosis/prognosis, novel therapies against AML, and treatment stratification of AML patients. During last year, we have continued to make advances in the project focussed on the requirement for specific proinflammatory signals to mediate the interaction of the mutant HSC with its niche. These data have been submitted to a highly regarded international scientific journal, and A. Villatoro will defend her PhD Thesis during 2020. In this work, we have demonstrated that defects in anti-inflammatory mechanisms that control inflammation lead to differentiation bias of HSC into the myeloid lineage. Unbalanced anti-inflammatory mechanisms are present in mouse models with aberrant RAS and in a subset of AML patients, and lead to aggravation of disease progression in transgenic mouse models. Further, we have used the anti-inflammatory defects as therapeutic targets in the NRAS-G12D+ mouse model of AML. We are currently investigating this therapy together with standard chemotherapy in a more aggressive MLL-AF9+ model of AML. Xenografts of leukemic HSC derived from patients showed promising therapeutic value of this drug for the subset of patients with anti-inflammatory defect. Thus, our data support that targeting the unbalanced anti-inflammation may be clinically relevant for a subset of AML patients, and it is our purpose to develop a clinical trial in the future where the AML patients most likely to benefit for this treatment are adequately selected based on disease molecular features. In 2019, the miljøstøtte of the group was renewed after positive feed-back by 4 experts in the field and internal evaluators, with a package of 12,5 million NOK, 2 postdocs and 1 technician. The group leader was invited as speaker to the Seminar Series at BRIC, Copenhagen, Denmark, by Bo Porse (Group Leader, Finsen Laboratory, Finsen Centre, Rigshospitalet, Copenhagen University Hospital) (05.09.2019). She also presented her research group work at the PhD course Molecular and Clinical Aspects of Cancer – MCAC (BIO-8302 & 8303). She was approached to peer review projects for prestigious international funding bodies like the Medical Research Council UK, and Research papers for high quality journals like Haematologica. She also continues as member of the Editorial Board of the Journal of Clinical Medicine (IF 5.583) Section Hematology. Student Dissertations: Adrian Florit Ruiz, ERASMUS BSc Student: Neuropatia de la medula osea en la leucemia mieloide aguda. Universitat Rovira i Virgili (Spain). Academic Grade A, 9.2/10. Golnaz Golnarnik, MSc Student: Neural Control in AML Development: Study of the Ultrastructure of Neuroglial Components of the Bone Marrow Microenvironment in a Mouse Model of Myeloid Leukemia. UiT - The Arctic University of Norway. Academic Grade C, 74.5/100.

Unfortunately, so far, there has been no substantial user participation in this Project, given the difficult logistics that we are facing to perform research with the animal facility closed down for almost three years, continuous delays in its reopening date with subsequent uncertainty for our group members, and the group split in two different locations with constant travels and complex coordination among group members. Discussion and interpretation of data to see ways forward must be performed when Experiments are confirmed to be reproducible and accurate, and this can be done from now. As soon as the animal facility reopens, during 2020, we will finally be able to involve the patients in 1) Taking part in Committees where the Project, its aims and main results will be discussed. All members of the Committee will provide comments/suggestions based on their AML experiences, and these will be considered for implementation for the future in the follow-up of the Project, and 2) Planning future Clinical Trial. The outcome of the present research has pinpointed a drug that may be beneficial for a subset of AML patients. This drug is FDA-approved, and used safely in unrelated diseases. This means that in the future, we will be able to apply for a Phase II/III Clinical Trial. Up to date, patients have been informed about the project to participate donating samples for research under our on-going REK.

2018
Our Group aims at understanding the molecular mechanisms of haematopoietic stem cell malignant transformation and the complex interactions of this cell With its surrounding microenvironment, With a focus on inflammation and signaling oncometabolites. Our goal is the identification of novel therapeutic targets for acute myeloid leukaemia (AML)AML is characterized by abnormal expansion of white blood cells. Intensive treatment with curative potential requires hospitalization during months with potential for life-threatening risks. Further, only about one-third of the patients are eligible for stem cell transplantation. Improving treatment strategies will require not only understanding the pathogenic mechanisms for AML development, but also its clinical complications and challenges. Survival advantage and differentiation blockade of haematopoietic stem cells (HSC) are required for AML Development. Interestingly, oncogenes that confer survival advantage to the HSC and are frequently mutated in human AML, such as RAS, only induce myeloproliferative neoplasms in mouse models. This indicates participation of additional factors. Until recently the focus has been on additional mutations With little consideration of the bone marrow HSC niche. The latter has an essential influence on haematopoiesis both under healthy conditions as well as in JAK2-V617+ myeloproliferation. In this context, our research will provide with knowledge of AML driving causes, and we will apply this knowledge in search of early markers for patient diagnosis/prognosis, and novel therapies against AML. During last year, we made great progress in one of our projects showing that imbalance of inflammation over anti-inflammatory mechanisms favors myeloid output and promotes malignancy in AML. Inflammation results in aggravation of disease progression in both transgenic mouse model of AML and xenografts of AML HSC obtained from patients. Further, defects in anti-inflammatory mechanisms that Control inflammation lead to differentiation bias of the HSC in otherwise healthy mice. We are currently investigating the effect of these defects in anti-inflammatory mechanisms on NRAS-G12D-driven disease. We are using the anti-inflammatory defects as therapeutic target in the NRAS-G12D+ mouse model of AML and in xenografts of leukaemic HSC derived from patients and transplanted into immunodeficient humanized mice. Preliminary data are promissing in this regard, so our data may pinpoint a novel therapeutic strategy against AML that could be easily translated in improved treatment for patients. The group leader was invited as speaker in the following international events to disseminate Research activity: 14.06.2018 YoungEHA Research Meeting, 24th Congress of the European Hematology Association, Stockholm. 04.05.2018 III Reunion del Grupo Espanol de Enfermedades Mieloproliferativas Cronicas Filadelfia Negativas (GEMFIN), Madrid. 09.02.2018 Seminar Series at Cancer Research UK Glasgow Center – Beatson Institute, Glasgow. She was approached to peer review projects for prestigious international funding bodies like the Medical Research Council UK, and Research papers for high quality journals like Haematologica. She was also invited to join the Editorial Board of the Journal of Clinical Medicine (IF 5.583) Section Hematology. Dissertations: I. Schmidt-Morgenroth - ERASMUS BSc: Potential role of intermediate metabolite succinate as mediator of intercellular communication in acute myeloid leukemia. Universite Clermont Auvergne (France) (A) J. Konieczny - MSc: Does ageing foster transformation to acute myeloid leukaemia? UiT - The Arctic University of Norway (A) R. Boydens - ERASMUS BSc: Role of TRAF6 in acute myeloid leukaemia development examined in vitro on NOMO-1 and THP-1 cell lines. VIVES University College (Belgium) (A)

User/Patient participation has been minor in this project so far, mainly due to the difficult logistics that we need to carry out Our Research ensuring excellence, together With the fact that we perform complex Experiments that require reproducibility before results can be interpreted and discussed. Up to date, patients have been informed about the project to participate donating samples for research under our on-going REK. I anticipate that during 2019, User/Patient participation in this Project will cover the following aspects 1) Taking part in Committees where the Project, its aims and main results will be discussed. All members of the Committee will provide comments/suggestions based on their AML experiences, and these will be considered for implementation within the Project; and hopefully 2) Planning future directions such as Clinical Trials. The outcome of the present research will be to pinpoint drugs that may target malignant cells specifically. Some of these drugs are FDA-approved, and used safely in unrelated diseases. This means that in the future, we should apply for a Phase II/III Clinical Trial

2017
Our research group “Stem Cell Aging and Cancer” aims at understanding the molecular mechanisms of haematopoietic stem cell malignant transformation and the complex interactions of this cell with its surrounding microenvironment, with a focus on inflammation and signaling oncometabolites. Our goal is the identification of novel therapeutic targets of potential clinical interest for acute myeloid leukaemia (AML).AML is a highly aggressive type of cancer, where abnormal white blood cells grow fast and accumulate inside the bone cavity. It is the most frequent acute leukaemia in adults, its incidence increases with age and the prognosis for the older patient remains bleak. Overcoming these problems will require better understanding of AML. It has been proposed that presence of several DNA mutations in haematopoietic stem cells is required for AML development. This suggestion is based on the fact that some of these lesions, when present as sole alterations, are only able to induce chronic blood disorders in mouse models but not the transition to AML. Indeed, this indicates that other factors must participate. These might comprise additional genetic lesions as previously suggested, but also specific alterations in the microenvironment that tightly controls the normal function of haematopoietic stem cells, which has received little consideration. Our primary aim is to investigate the potential role of such signaling dysfunctions in AML pathogenesis and their importance to human AML. For these studies, we are using human patient material, and data is being validated in vivo using genetically engineered mouse models expressing AML driver genes. Signaling intermediates are controlled in vivo using drugs and additional genetic engineering, allowing their potential value to be tested in novel therapeutic strategies. Thus, the present research will give insights into the basic processes that regulate haematopoietic stem cell function/dysfunction, and will allow the application of this knowledge to provide a novel platform for more efficient therapies against AML. The group is led by Dr. Lorena Arranz, who joined the Department of Medical Biology at the University of Tromsø (UiT) as Group Leader and NCMM Young Associate Investigator in November 2014, and was appointed as member of the Department of Haematology at the University Hospital of North Norway (UNN) in January 2015. Currently, the group is formed by three postdocs (Natalya Seredkina, Aurora Bernal, Franco Grimolizzi), one PhD student (Alicia Villatoro), two engineers (Liv Tone Eliassen, Almudena Tello) and a MSc Student (Joanna Konieczny). Lorena Arranz is supported by a joint meeting among UiT, UNN, and the Regional Authorities of Northern Norway, Young Research Talent grants from the Norwegian Research Council (Stem Cell and FRIPRO programs), the Norwegian Cancer Society, the Aakres Foundation, the NCMM and the Regional Authorities of Northern Norway. During 2017, I have participated as speaker in several seminar series and scientific meetings: 06.02.2017 NCMM Network Meeting, Oslo, Norway. Invited by Kjetil Tasken, Institute Director. 08.02.2017 Department of Microbiology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway. Invited by Arne Klungland, Head of Research Section. 03.03.2017 Department of Medical Biology, Faculty of Health Sciences, UiT, Tromsø, Norway. 27-30.04.2017 Workshop at Hurtigruta. Invited by Ole P. Rekvig. 04-07.09.2017 Nordic EMBL Partnership for Molecular Medicine Annual Meeting, Helsinki, Finland, where A. Bernal presented a poster. 06-07.11.2017 NCMM Retreat, Larvik, Norway, where we presented 2 posters and 2 oral presentations, and we won the award to the best poster. We have also participated in local activities, including the following: 12.09.2017 Snakk med en forsker Open Day at UiT, where A. Bernal presented a Poster outlining her research. In addition, we actively take part at the NCMM weekly seminars, where we presented 2 seminars last year.
Vitenskapelige artikler
Villatoro A, Cuminetti V, Bernal A, Torroja C, Cossío I, Benguría A, Ferré M, Konieczny J, Vázquez E, Rubio A, Utnes P, Tello A, You X, Fenton CG, Paulssen RH, Zhang J, Sánchez-Cabo F, Dopazo A, Vik A, Anderssen E, Hidalgo A, Arranz L

Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation.

Nat Commun 2023 Jan 03;14(1):12. Epub 2023 jan 3

PMID: 36596811

Vilaplana-Lopera N, Cuminetti V, Almaghrabi R, Papatzikas G, Rout AK, Jeeves M, González E, Alyahyawi Y, Cunningham A, Erdem A, Schnütgen F, Raghavan M, Potluri S, Cazier JB, Schuringa JJ, Reed MAC, Arranz L, Günther UL, Garcia P

Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells.

Elife 2022 Sep 02;11(). Epub 2022 sep 2

PMID: 36052997

Martínez de Toda I, Rattan SIS, De la Fuente M, Arranz L

Female Mice Reaching Exceptionally High Old Age Have Preserved 20S Proteasome Activities.

Antioxidants (Basel) 2021 Aug 31;10(9). Epub 2021 aug 31

PMID: 34573029

Villatoro A, Konieczny J, Cuminetti V, Arranz L

Leukemia Stem Cell Release From the Stem Cell Niche to Treat Acute Myeloid Leukemia.

Front Cell Dev Biol 2020;8():607. Epub 2020 jul 9

PMID: 32754595

Cuminetti V, Arranz L

Bone Marrow Adipocytes: The Enigmatic Components of the Hematopoietic Stem Cell Niche.

J Clin Med 2019 May 18;8(5). Epub 2019 mai 18

PMID: 31109063

Konieczny J, Arranz L

Updates on Old and Weary Haematopoiesis.

Int J Mol Sci 2018 Aug 29;19(9). Epub 2018 aug 29

PMID: 30158459

Grimolizzi F, Arranz L

Multiple faces of succinate beyond metabolism in blood.

Haematologica 2018 Oct;103(10):1586-1592. Epub 2018 jun 28

PMID: 29954939

Bernal A, Arranz L

Nestin-expressing progenitor cells: function, identity and therapeutic implications.

Cell Mol Life Sci 2018 06;75(12):2177-2195. Epub 2018 mar 14

PMID: 29541793

Arranz L, Arriero MDM, Villatoro A

Interleukin-1β as emerging therapeutic target in hematological malignancies and potentially in their complications.

Blood Rev 2017 Sep;31(5):306-317. Epub 2017 mai 3

PMID: 28495184

#Villatoro A, #Cuminetti V, Bernal A, Torroja C, Cossío I, Benguría A, Ferré M, Konieczny J, Vázquez E, Rubio A, Utnes P, You X, Fenton CG, Paulssen RH, Zhang J, Sánchez-Cabo F, Dopazo A, Vik A, Anderssen E, Hidalgo A & Arranz L. #Equal contribution

Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation

Nature Communications volume 14, Article number: 12 (2023)

Arranz, L

The Hematology of Tomorrow Is Here—Preclinical Models Are Not: Cell Therapy for Hematological Malignancies

Cancers 2022, 14(3), 580; https://doi.org/10.3390/cancers14030580

Dhivya Thiyagarajan, Hege L. Pedersen, Natalya Seredkina, Kjersti D. Horvei, Lorena Arranz, Ramon Sonneveld, Tom Nijenhuis, Johan van der Vlag, Ole P. Rekvig

IL-1b Promotes a New Function of DNase I as a Transcription Factor for the Fas Receptor Gene

Front. Cell Dev. Biol. 2018. 6:7. doi: 10.3389/fcell.2018.00007

Doktorgrader
Alicia Villatoro

The role of interleukin-1 receptor antagonist in normal and malignant hematopoiesis

Disputert:
september 2022
Hovedveileder:
Lorena Arranz
Deltagere
  • Marc Ferre Doktorgradsstipendiat
  • Samuel Geiseler Prosjektdeltaker
  • Marko Ristic Postdoktorstipendiat
  • Peter Andree Utnes Postdoktorstipendiat
  • Lorena Arranz Prosjektleder
  • Luis Miguel Gonzalez Alonso Prosjektdeltaker
  • Almudena Tello Prosjektdeltaker
  • Liv Tone Eliassen Prosjektdeltaker
  • Golnaz Golnarnik Prosjektdeltaker
  • Joanna Konieczny Doktorgradsstipendiat
  • Alicia Elena Villatoro González Doktorgradsstipendiat
  • Aurora Bernal Mera Postdoktorstipendiat
  • Vincent Cuminetti Postdoktorstipendiat
  • Alicia Villatoro Doktorgradsstipendiat
  • Franco Grimolizzi Postdoktorstipendiat
  • Natalya Seredkina Postdoktorstipendiat
  • Aurora Bernal Postdoktorstipendiat

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