ORCID Profile
0000-0002-3012-9273
Current Organisations
University of Melbourne
,
Peter MacCallum Cancer Centre
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Publisher: Informa UK Limited
Date: 13-02-2017
Publisher: American Society of Hematology
Date: 09-10-2020
DOI: 10.1182/BLOODADVANCES.2020002708
Abstract: A novel KMT2A-rearrangement, MLL-TFE3, was identified in an infant leukemia patient. MLL-TFE3 expression produces aggressive leukemia in a mouse model.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541185.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541191.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541179.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541167
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541170.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541173.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541194.V1
Abstract: Supplementary Figure from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541182
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549562.V1
Abstract: Abstract Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies. Significance: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. i This article is highlighted in the In This Issue feature, p. 1397 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541188
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541164
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541185
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541188.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541167.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541182.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Elsevier BV
Date: 05-2017
Publisher: American Association for Cancer Research (AACR)
Date: 12-01-2021
DOI: 10.1158/2159-8290.CD-20-0738
Abstract: FLT3-ITD mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine biosynthesis, thereby rendering FLT3-ITD–driven leukemias dependent upon serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-ITD–driven AMLs to chemotherapy. This article is highlighted in the In This Issue feature, p. 1307
Publisher: American Society of Hematology
Date: 07-04-2022
DOI: 10.1182/BLOODADVANCES.2021006076
Abstract: Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype of B-cell ALL characterized by a gene expression profile resembling Philadelphia chromosome–positive ALL (Ph+ ALL) in the absence of BCR-ABL1. Tyrosine kinase–activating fusions, some involving ABL1, are recurrent drivers of Ph-like ALL and are targetable with tyrosine kinase inhibitors (TKIs). We identified a rare instance of SFPQ-ABL1 in a child with Ph-like ALL. SFPQ-ABL1 expressed in cytokine-dependent cell lines was sufficient to transform cells and these cells were sensitive to ABL1-targeting TKIs. In contrast to BCR-ABL1, SFPQ-ABL1 localized to the nuclear compartment and was a weaker driver of cellular proliferation. Phosphoproteomics analysis showed upregulation of cell cycle, DNA replication, and spliceosome pathways, and downregulation of signal transduction pathways, including ErbB, NF-κB, vascular endothelial growth factor (VEGF), and MAPK signaling in SFPQ-ABL1–expressing cells compared with BCR-ABL1–expressing cells. SFPQ-ABL1 expression did not activate phosphatidylinositol 3-kinase rotein kinase B (PI3K/AKT) signaling and was associated with phosphorylation of G2/M cell cycle proteins. SFPQ-ABL1 was sensitive to navitoclax and S-63845 and promotes cell survival by maintaining expression of Mcl-1 and Bcl-xL. SFPQ-ABL1 has functionally distinct mechanisms by which it drives ALL, including subcellular localization, proliferative capacity, and activation of cellular pathways. These findings highlight the role that fusion partners have in mediating the function of ABL1 fusions.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549562
Abstract: Abstract Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies. Significance: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. i This article is highlighted in the In This Issue feature, p. 1397 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541176.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541179
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.NEUBIOREV.2018.02.006
Abstract: To summarize all current studies focusing on blood biomarkers in paediatric mild traumatic brain injury (mTBI) and to outline the possible use of blood biomarkers for diagnostic, prognostic and monitoring purposes within this setting. A systematic review following the PRISMA guidelines was conducted using the MEDLINE, PubMed and EMBASE databases. A total of 21 studies were included in the review, encompassing a total of 14 different biomarkers. Seventeen (81%) of these studies found a significant association between biomarker concentration and mTBI characteristics, however results from studies to date are erse and at times conflicting. GFAP appears to be a promising blood biomarker for the prognosis and monitoring of mTBI, whereas UCH-L1 appears more promising at mTBI diagnosis. Despite this, the overall heterogeneity in assessed biomarkers, study design and measurement tools has made drawing specific conclusions challenging. Future research will require more uniform study design and methodological approaches to allow for the comparison, corroboration and validation of blood biomarkers within the context of paediatric mTBI.
Publisher: American Association for Cancer Research (AACR)
Date: 21-03-2022
DOI: 10.1158/2159-8290.CD-20-1145
Abstract: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. This article is highlighted in the In This Issue feature, p. 1397
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541173
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541194
Abstract: Supplementary Figure from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541170
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Elsevier BV
Date: 06-2021
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541176
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Elsevier BV
Date: 05-2021
Publisher: Cold Spring Harbor Laboratory
Date: 27-05-2020
DOI: 10.1101/2020.05.26.116392
Abstract: Activating FMS-like tyrosine kinase 3 ( FLT3 ) mutations occur in approximately 30% of all acute myeloid leukaemias (AMLs) and are associated with poor prognosis. The limited clinical efficacy of FLT3 inhibitor monotherapy has highlighted the need for alternative therapeutic targets and treatments for FLT3-mutant AML. Using human and murine models of MLL-rearranged AML harbouring FLT3 internal tandem duplication (FLT3-ITD) and primary patient s les, we have demonstrated that FLT3-ITD promotes serine uptake and serine synthesis via transcriptional regulation of neutral amino acid transporters ( SLC1A4 and SLC1A5 ) and genes in the de novo serine synthesis pathway ( PHGDH and PSAT1 ). Mechanistically, dysregulation of serine metabolism in FLT3-mutant AML is dependent on the mTORC1-ATF4 axis, that drives RNA-Pol II occupancy at PHGDH, PSAT1, SLC1A4 and SLC1A5 . Genetic or pharmacological inhibition of the de novo serine synthesis pathway selectively inhibited the proliferation of FLT3-ITD AML cells, and this was potentiated by withdrawal of exogenous serine. Purine supplementation effectively rescued the antiproliferative effect of inhibiting de novo serine synthesis, consistent with the idea that serine fuels purine nucleotide synthesis in FLT3-mutant AML. Pharmacological inhibition of the de novo serine synthesis pathway, using the PHGDH inhibitor WQ-2101, sensitises FLT3-mutant AML cells to the standard of care chemotherapy agent cytarabine via exacerbation of DNA damage. Collectively, these data reveal new insights as to how FLT3 mutations reprogram metabolism in AML, and reveal a combination therapy strategy to improve the treatment of FLT3-mutant AML. FLT3 mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine metabolism, thereby rendering FLT3-ITD leukemias dependent on serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-mutant AML to chemotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541191
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541164.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
No related grants have been discovered for Stefan Bjelosevic.