Kimberley Joanne Hatfield

Haukeland University Hospital

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Øystein Bruserud

University of Bergen

Håkon Reikvam

Haukeland University Hospital

Bjørn Tore Gjertsen

University of Bergen

Ina Nepstad

Consortium of European Social Science Data Archives

Elisabeth Ersvær

Inland Norway University of Applied Sciences

Ida Sofie Grønningsæter

University of Bergen

Anita Ryningen

Western Norway University of Applied Sciences

Anne M. Øyan

University of Bergen

Kristin Paulsen Rye

University of Bergen

Astrid Olsnes Kittang

Haukeland University Hospital

Cooperative Institutions

University of Bergen

Haukeland University Hospital

Harvard University

Massachusetts General Hospital

Weatherford College

University of Oslo

Oslo University Hospital

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Massachusetts Institute of Technology

Centre National de la Recherche Scientifique

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NPM1-Mutated Patient-Derived AML Cells Are More Vulnerable to Rac1 Inhibition

Biomedicines (2022)

Anette Lodvir Hemsing Kristin Paulsen Rye Kimberley Joanne Hatfield Håkon Reikvam

The prognosis of acute myeloid leukemia (AML) is poor, especially for the elderly population. Targeted therapy with small molecules may be a potential strategy to overcome chemoresistance and improve survival in AML. We investigated the inhibition of the signaling molecule ras-related C3 botulinum toxin substrate 1 (Rac1) in leukemia cells derived from 79 consecutive AML patients, using five Rac1 inhibitors: ZINC69391, ITX3, EHOP-016, 1A-116, and NSC23766. In vitro cell proliferation and apoptosis assays and the assessment of cytokine profiles in culture media were conducted. All five inhibitors had an antiproliferative effect; IC50 ranged from 3−24 µM. They induced significant apoptosis and necrosis compared to the untreated controls (p < 0.0001) at concentrations around IC40 and IC80. A high versus an intermediate or low antiproliferative effect was more common in NPM1-mutated (p = 0.002) and CD34-negative (p = 0.008) samples, and when NPM1 and FLT3 (p = 0.027) were combined. Presence of NPM1 mutation was associated with reduced viability after treatment with EHOP-016 (p = 0.014), ITX3 (p = 0.047), and NSC23766 (p = 0.003). Several cytokines crucial for leukemogenesis were reduced after culture, with the strongest effects observed for 1A-116 and NSC23766. Our findings suggest potent effects of Rac1 inhibition in primary AML cells and, interestingly, samples harboring NPM1 mutation seem more vulnerable.

NPM1

Viability assay

10.3390/biomedicines10081881

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Citations (7)

Emerging therapeutic targets for the treatment of human acute myeloid leukemia (part 1) – gene transcription, cell cycle regulation, metabolism and intercellular communication

Expert Review of Hematology (2015)

Håkon Reikvam Michelle Hauge Annette K. Brenner Kimberley Joanne Hatfield Øystein Bruserud

Human acute myeloid leukemia is a heterogeneous disease and the effect of therapeutic targeting of specific molecular mechanisms will probably vary between patient subsets. Cell cycle regulators are among the emerging targets (e.g., aurora and polo-like kinases, cyclin-dependent kinases). Inhibition of communication between acute myeloid leukemia and stromal cells is also considered; among the most promising of these strategies are inhibition of hedgehog-initiated, CXCR4–CXCL12 and Axl-Gas6 signaling. Finally, targeting of energy and protein metabolism is considered, the most promising strategy being inhibition of isocitrate dehydrogenase in patients with IDH mutations. Thus, several strategies are now considered, and a major common challenge for all of them is to clarify how they should be combined with each other or with conventional chemotherapy, and whether their use should be limited to certain subsets of patients.

10.1586/17474086.2015.1032935

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Citations (16)

Pretransplant Systemic Lipidomic Profiles in Allogeneic Stem Cell Transplant Recipients

Cancers (2022)

Kimberley Joanne Hatfield Øystein Bruserud Håkon Reikvam

Allogeneic stem cell transplantation is used in the treatment of high-risk hematological malignancies. However, this treatment is associated with severe treatment-related morbidity and mortality. The metabolic status of the recipient may be associated with the risk of development of transplant-associated complications such as graft-versus-host disease (GVHD). To better understand the impact of the lipidomic profile of transplant recipients on posttransplant complications, we evaluated the lipid signatures of patients with hematological disease using non-targeted lipidomics. In the present study, we studied pretransplant serum samples derived from 92 consecutive patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). A total of 960 lipid biochemicals were identified, and the pretransplant lipidomic profiles differed significantly when comparing patients with and without the risk factors: (i) pretransplant inflammation, (ii) early fluid overload, and (iii) patients with and without later steroid-requiring acute GVHD. All three factors, but especially patients with pretransplant inflammation, were associated with decreased levels of several lipid metabolites. Based on the overall concentrations of various lipid subclasses, we identified a patient subset characterized by low lipid levels, increased frequency of MDS patients, signs of inflammation, decreased body mass index, and an increased risk of early non-relapse mortality. Metabolic targeting has been proposed as a possible therapeutic strategy in allotransplant recipients, and our present results suggest that the clinical consequences of therapeutic intervention (e.g., nutritional support) will also differ between patients and depend on the metabolic context.

Lipid Profile

10.3390/cancers14122910

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Granulocyte colony-stimulating factor alters the systemic metabolomic profile in healthy donors

Metabolomics (2016)

Kimberley Joanne Hatfield Guro Kristin Melve Øystein Bruserud

Peripheral blood stem cells mobilized by granulocyte colony-stimulating factor (G-CSF) from healthy donors are commonly used for allogeneic stem cell transplantation. The effect of G-CSF administration on global serum metabolite profiles has not been investigated before.This study aims to examine the systemic metabolomic profiles prior to and following administration of G-CSF in healthy adults.Blood samples were collected from 15 healthy stem cell donors prior to and after administration of G-CSF 10 µg/kg/day for 4 days. Using a non-targeted metabolomics approach, metabolite levels in serum were determined using ultrahigh performance liquid chromatography-tandem mass spectrometry and gas chromatography/mass spectrometry.Comparison of the metabolite profiles of donors before and after G-CSF treatment revealed 239 metabolites that were significantly altered. The major changes of the metabolite profiles following G-CSF administration included alteration of several fatty acids, including increased levels of several medium and long-chain fatty acids, as well as polyunsaturated fatty acids; while there were lower levels of other lipid metabolites such as phospholipids, lysolipids, sphingolipids. Furthermore, there were significantly lower levels of several amino acids and/or their metabolites, including several amino acids with known immunoregulatory functions (methionine, tryptophan, valine). Lastly, the levels of several nucleotides and nucleotide metabolites (guanosine, adenosine, inosine) were also decreased after G-CSF administration, while methylated products were increased. Some of these altered products/metabolites may potentially have angioregulatory effects whereas others may suggest altered intracellular epigenetic regulation.Our results show that G-CSF treatment alters biochemical serum profiles, in particular amino acid, lipid and nucleotide metabolism. Additional studies are needed to further evaluate the relevance of these changes in healthy donors.

Inosine

Metabolome

Sphingolipid

10.1007/s11306-016-1139-x

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Citations (15)

Coculture of native human acute myelogenous leukemia blasts with fibroblasts and osteoblasts results in an increase of vascular endothelial growth factor levels

European Journal Of Haematology (2004)

Nils Glenjen Kimberley Joanne Hatfield Øystein Bruserud

Abstract: Objectives : Angiogenesis seems important in the development of acute myelogenous leukemia (AML). Proangiogenic vascular endothelial growth factor (VEGF) is constitutively secreted by the AML blasts for a subset of patients, but it can also be released by non‐leukemic bone marrow cells. Methods : VEGF levels were determined after coculture of native human AML blasts with fibroblast lines, osteoblastic sarcoma cell lines, normal bone marrow stromal cells and normal osteoblasts. Cultures were prepared with leukemic and non‐leukemic cells separated by a semipermeable membrane or in direct contact. Results : The non‐leukemic cells usually showed higher spontaneous VEGF release than AML cell populations. Coculture of AML blasts with HFL1 fibroblasts caused a supra‐additive increase of VEGF levels when the cell populations were cultured separately, and the increase was also observed when cells were cultured in direct contact. An increase was also observed when AML blasts were cultured with osteoblastic sarcoma cells, normal bone marrow stromal cells and normal osteoblasts. Coculture had divergent effects on VEGF mRNA levels both for leukemic and non‐leukemic cells, but increased mRNA levels were commonly observed especially for the non‐leukemic cells. Cytokine inhibition experiments suggest that IL1 is important for the VEGF‐increasing crosstalk, whereas the mechanisms are probably heterogeneous for coculture with osteoblasts. Conclusion : The bi‐directional crosstalk via local cytokine networks between AML blasts and non‐leukemic cells results in increased local VEGF levels, an observation suggesting that VEGF‐targeting antiangiogenic therapy should be considered as a general therapeutic strategy in AML.

10.1111/j.1600-0609.2004.00333.x

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Citations (20)

Pretransplant systemic metabolic profiles in allogeneic hematopoietic stem cell transplant recipients - identification of patient subsets with increased transplant-related mortality

Transplantation and Cellular Therapy (2023)

Håkon Reikvam Øystein Bruserud Kimberley Joanne Hatfield

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used in the treatment of high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); however, the treatment has high risk of severe transplantation-related mortality (TRM). In this study, we examined pretransplantation serum samples derived from 92 consecutive allotransplant recipients with AML or MDS. Using nontargeted metabolomics, we identified 1274 metabolites including 968 of known identity (named biochemicals). We further investigated metabolites that differed significantly when comparing patients with and without early extensive fluid retention, pretransplantation inflammation (both being associated with increased risk of acute graft-versus-host disease [GVHD]/nonrelapse mortality) and development of systemic steroid-requiring acute GVHD (aGVHD). All three factors are associated with TRM and were also associated with significantly altered amino acid metabolism, although there was only a minor overlap between these three factors with regard to significantly altered individual metabolites. Furthermore, steroid-requiring aGVHD was especially associated with altered taurine/hypotaurine, tryptophan, biotin, and phenylacetate metabolism together with altered malate-aspartate shuttle and urea cycle regulation. In contrast, pretransplantation inflammation was associated with a weaker modulation of many different metabolic pathways, whereas extensive fluid retention was associated with a weaker modulation of taurine/hypotaurine metabolism. An unsupervised hierarchical cluster analysis based on the 13 most significantly identified metabolites associated with aGVHD identified a patient subset with high metabolite levels and increased frequencies of MDS/MDS-AML, steroid-requiring aGVHD and early TRM. On the other hand, a clustering analysis based on metabolites that were significantly altered for aGVHD, inflammation, and fluid retention comparison groups identified a patient subset with a highly significant association with TRM. Our study suggests that the systemic pretransplantation metabolic profiles can be used to identify patient subsets with an increased frequency of TRM.

Hypotaurine

10.1016/j.jtct.2023.03.020

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Citations (6)

Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity

Journal of Personalized Medicine (2021)

Ida Sofie Grønningsæter Håkon Reikvam Elise Aasebø Sushma Bartaula-Brevik Maria Hernandez-Valladares

Autophagy is a highly conserved cellular degradation process that prevents cell damage and promotes cell survival, and clinical efforts have exploited autophagy inhibition as a therapeutic strategy in cancer. Chloroquine is a well-known antimalarial agent that inhibits late-stage autophagy. We evaluated the effects of chloroquine on cell viability and proliferation of acute myeloid leukemia acute myeloid leukemia (AML) cells derived from 81 AML patients. Our results show that chloroquine decreased AML cell viability and proliferation for the majority of patients. Furthermore, a subgroup of AML patients showed a greater susceptibility to chloroquine, and using hierarchical cluster analysis, we identified 99 genes upregulated in this patient subgroup, including several genes related to leukemogenesis. The combination of chloroquine with low-dose cytarabine had an additive inhibitory effect on AML cell proliferation. Finally, a minority of patients showed increased extracellular constitutive mediator release in the presence of chloroquine, which was associated with strong antiproliferative effects of chloroquine as well as cytarabine. We conclude that chloroquine has antileukemic activity and should be further explored as a therapeutic drug against AML in combination with other cytotoxic or metabolic drugs; however, due to the patient heterogeneity, chloroquine therapy will probably be effective only for selected patients.

10.3390/jpm11080779

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Citations (13)

Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy

Cells (2019)

Ida Sofie Grønningsæter Hanne Fredly Bjørn Tore Gjertsen Kimberley Joanne Hatfield Øystein Bruserud

Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (p < 0.05, q < 0.05), where the majority of altered metabolites belonged to lipid (especially fatty acid metabolism) and amino acid pathways, including several carnitines. These metabolomic effects, and especially the effects on lipid metabolism, may be important for the antileukemic and epigenetic effects of this treatment.

Valproic Acid

Fatty Acid Metabolism

Tretinoin

10.3390/cells8101229

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Citations (25)

Increased antileukemic effects in human acute myeloid leukemia by combining HSP70 and HSP90 inhibitors

Expert Opinion on Investigational Drugs (2013)

Håkon Reikvam Ina Nepstad André Sulen Bjørn Tore Gjertsen Kimberley Joanne Hatfield

Background: Heat shock proteins (HSPs) are molecular chaperones that assist proteins in their folding to native structures. HSP90, and more recently HSP70, have emerged as possible therapeutic targets in human malignancies, including acute myeloid leukemia (AML). Design and methods: The authors investigated the effects of the HSP70 inhibitor VER-155008 tested alone or in combination with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) on proliferation, viability, constitutive cytokine release and intracellular HSP levels of primary human AML cells. Results: VER-155008 caused a dose-dependent inhibition of cytokine-dependent AML cell proliferation both in suspension cultures and in a colony formation assay, and the drug also had a proapoptotic effect. HSP70 and HSP90 inhibition had additive antiproliferative and proapoptotic effects. VER-155008 caused a strong inhibition of the constitutive AML cell release of several growth factors/regulators of hematopoiesis (i.e., TNF-α, VEGF, IL-3, IL-1β, IL-1 receptor antagonist), but had relatively weak effects on the constitutive chemokine release. HSP70 inhibition did not induce any compensatory increase of other HSPs. Conclusion: HSP70 inhibition has antileukemic effects when tested alone, and the combination of HSP70 and HSP90 inhibition seems to have additive antileukemic effects for primary human AML cells in vitro.

10.1517/13543784.2013.791280

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Citations (30)

Serum levels of endothelium-derived endocan are increased in patients with untreated acute myeloid leukemia

Hematology (2011)

Kimberley Joanne Hatfield Philippe Lassalle Rafael Alexander Leiva Roald Lindås Øystein Wendelboe

Endocan is a soluble proteoglycan expressed only by vascular endothelium and is also found circulating in the bloodstream. Inflammatory cytokines as well as proangiogenic growth factors increase its expression, and increased serum levels are found in immunocompetent patients with sepsis. We investigated serum endocan levels in patients with untreated acute myeloid leukemia (AML) and AML patients during chemotherapy-induced bone marrow failure. We observed increased levels in 40 AML patients compared with healthy controls, which was also confirmed in a second cohort. The serum levels decreased after intensive chemotherapy and subsequent severe chemotherapy-induced cytopenia, and increased levels were thereafter observed during bone marrow regeneration. However, even for these severely immunocompromized patients, serum endocan levels increased during complicating bacterial infections before a decrease was seen during antibiotic therapy. To conclude, serum endocan is a disease marker in AML, but serum levels are also affected by complicating infections and bone marrow regeneration.

Cytopenia

10.1179/102453311x13127324303434

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Citations (41)