Publications by authors named "Aaron D Schimmer"

189 Publications

Novel subtypes of -mutated AML with distinct outcome.

Mol Cell Oncol 2021 30;8(4):1924600. Epub 2021 Jun 30.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Acute myeloid leukemia (AML) is heterogeneous with one common subtype recognized by the presence of recurrent mutation of nucleophosmin-1 (). Emerging evidence indicates that within mutated AML there is variation in outcome which challenges how best to characterize and treat the individual patient. Our recent findings show that there are two distinct (primitive and committed) subtypes within mutated AML patients. These subtypes exhibit specific molecular characteristics, disease differentiation states, patient survival, and differential drug responses.
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http://dx.doi.org/10.1080/23723556.2021.1924600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489904PMC
June 2021

Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.

Blood 2021 07;138(3):234-245

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼70% of treatment-naive elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that venetoclax directly activated T cells to increase their cytotoxicity against acute myeloid leukemia (AML) in vitro and in vivo. Venetoclax enhanced T-cell effector function by increasing reactive oxygen species generation through inhibition of respiratory chain supercomplexes formation. In addition, azacytidine induced a viral mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T cell-mediated cytotoxicity. Similar findings were seen in patients treated with venetoclax, as this treatment increased reactive oxygen species generation and activated T cells. Collectively, this study presents a new immune-mediated mechanism of action for venetoclax and azacytidine in the treatment of AML and highlights a potential combination of venetoclax and adoptive cell therapy for patients with AML.
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http://dx.doi.org/10.1182/blood.2020009081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310428PMC
July 2021

Mitochondrial ATP-Dependent Proteases-Biological Function and Potential Anti-Cancer Targets.

Cancers (Basel) 2021 Apr 22;13(9). Epub 2021 Apr 22.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.

Cells must eliminate excess or damaged proteins to maintain protein homeostasis. To ensure protein homeostasis in the cytoplasm, cells rely on the ubiquitin-proteasome system and autophagy. In the mitochondria, protein homeostasis is regulated by mitochondria proteases, including four core ATP-dependent proteases, m-AAA, i-AAA, LonP, and ClpXP, located in the mitochondrial membrane and matrix. This review will discuss the function of mitochondrial proteases, with a focus on ClpXP as a novel therapeutic target for the treatment of malignancy. ClpXP maintains the integrity of the mitochondrial respiratory chain and regulates metabolism by degrading damaged and misfolded mitochondrial proteins. Inhibiting ClpXP genetically or chemically impairs oxidative phosphorylation and is toxic to malignant cells with high ClpXP expression. Likewise, hyperactivating the protease leads to increased degradation of ClpXP substrates and kills cancer cells. Thus, targeting ClpXP through inhibition or hyperactivation may be novel approaches for patients with malignancy.
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http://dx.doi.org/10.3390/cancers13092020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122244PMC
April 2021

Very long chain fatty acid metabolism is required in acute myeloid leukemia.

Blood 2021 Jun;137(25):3518-3532

Department of Food Science, University of Guelph, Guelph, ON, Canada.

Acute myeloid leukemia (AML) cells have an atypical metabolic phenotype characterized by increased mitochondrial mass, as well as a greater reliance on oxidative phosphorylation and fatty acid oxidation (FAO) for survival. To exploit this altered metabolism, we assessed publicly available databases to identify FAO enzyme overexpression. Very long chain acyl-CoA dehydrogenase (VLCAD; ACADVL) was found to be overexpressed and critical to leukemia cell mitochondrial metabolism. Genetic attenuation or pharmacological inhibition of VLCAD hindered mitochondrial respiration and FAO contribution to the tricarboxylic acid cycle, resulting in decreased viability, proliferation, clonogenic growth, and AML cell engraftment. Suppression of FAO at VLCAD triggered an increase in pyruvate dehydrogenase activity that was insufficient to increase glycolysis but resulted in adenosine triphosphate depletion and AML cell death, with no effect on normal hematopoietic cells. Together, these results demonstrate the importance of VLCAD in AML cell biology and highlight a novel metabolic vulnerability for this devastating disease.
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http://dx.doi.org/10.1182/blood.2020008551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225921PMC
June 2021

Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free ALL Regimen.

Curr Oncol 2020 12 22;28(1):128-137. Epub 2020 Dec 22.

Princess Margaret Cancer Centre, Department of Medical Oncology and Hematology, University Health Network, Toronto, ON M5G 2C1, Canada.

Background: venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL), especially in patients treated with asparaginase (ASNase)-including regiments. However, VTE risk in adult Philadelphia-positive ALL (Ph+ve ALL) patients treated with non-hyperCVAD chemotherapy is unclear. In this study, we examined VTE incidence in adult Ph+ve ALL patients treated with imatinib plus a pediatric-inspired asparaginase (ASNase)-free regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol.

Methods: a single centre retrospective review of Ph+ve ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008-2019 with imatinib plus modified DFCI protocol was conducted.

Results: of the 123 patients included, 30 (24.3%) had at least 1 radiology confirmed VTE event from diagnosis to the end of maintenance therapy. 86.7% (26/30) of the VTE events occurred during active treatment. Of all VTE events, the majority (53.3%) were DVT and/or PE while another significant portion were catheter-related (40.0%). Major bleeding was observed in 1 patient on VTE treatment with low molecular weight heparin (LMWH).

Conclusion: a high VTE incidence (24.3%) was observed in adults Ph+ve ALL patients treated with imatinib plus an ASNase-free modified DFCI pediatric ALL protocol, suggesting prophylactic anticoagulation should be considered for all adult Ph+ve ALL patients including those treated with ASNase-free regimens.
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http://dx.doi.org/10.3390/curroncol28010016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816186PMC
December 2020

Biological and therapeutic implications of a unique subtype of NPM1 mutated AML.

Nat Commun 2021 02 16;12(1):1054. Epub 2021 Feb 16.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. AML with NPM1 mutation is a distinct genetic entity in the revised World Health Organization classification. However, differing patterns of co-mutation and response to therapy within this group necessitate further stratification. Here we report two distinct subtypes within NPM1 mutated AML patients, which we label as primitive and committed based on the respective presence or absence of a stem cell signature. Using gene expression (RNA-seq), epigenomic (ATAC-seq) and immunophenotyping (CyToF) analysis, we associate each subtype with specific molecular characteristics, disease differentiation state and patient survival. Using ex vivo drug sensitivity profiling, we show a differential drug response of the subtypes to specific kinase inhibitors, irrespective of the FLT3-ITD status. Differential drug responses of the primitive and committed subtype are validated in an independent AML cohort. Our results highlight heterogeneity among NPM1 mutated AML patient samples based on stemness and suggest that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, could have therapeutic benefit.
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http://dx.doi.org/10.1038/s41467-021-21233-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886883PMC
February 2021

Mitochondrial and Metabolic Pathways Regulate Nuclear Gene Expression to Control Differentiation, Stem Cell Function, and Immune Response in Leukemia.

Cancer Discov 2021 05 27;11(5):1052-1066. Epub 2021 Jan 27.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Mitochondria are involved in many biological processes including cellular homeostasis, energy generation, and apoptosis. Moreover, mitochondrial and metabolic pathways are interconnected with gene expression to regulate cellular functions such as cell growth, survival, differentiation, and immune recognition. Metabolites and mitochondrial enzymes regulate chromatin-modifying enzymes, chromatin remodeling, and transcription regulators. Deregulation of mitochondrial pathways and metabolism leads to alterations in gene expression that promote cancer development, progression, and evasion of the immune system. This review highlights how mitochondrial and metabolic pathways function as a central mediator to control gene expression, specifically on stem cell functions, differentiation, and immune response in leukemia. SIGNIFICANCE: Emerging evidence demonstrates that mitochondrial and metabolic pathways influence gene expression to promote tumor development, progression, and immune evasion. These data highlight new areas of cancer biology and potential new therapeutic strategies.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1227DOI Listing
May 2021

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity.

JCI Insight 2021 03 8;6(5). Epub 2021 Mar 8.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase I clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 (BEND3), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243 in vitro and in vivo. Knockout of BEND3 dampened TAK-243 effects on ubiquitylation, proteotoxic stress, and DNA damage response. BEND3 knockout upregulated the ATP-binding cassette efflux transporter breast cancer resistance protein (BCRP; ABCG2) and reduced the intracellular levelsof TAK-243. TAK-243 sensitivity correlated with BCRP expression in cancer cell lines of different origins. Moreover, chemical inhibition and genetic knockdown of BCRP sensitized intrinsically resistant high-BCRP cells to TAK-243. Thus, our data demonstrate that BEND3 regulates the expression of BCRP for which TAK-243 is a substrate. Moreover, BCRP expression could serve as a predictor of TAK-243 sensitivity.
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http://dx.doi.org/10.1172/jci.insight.141518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021101PMC
March 2021

Transduction of Primary AML Cells with Lentiviral Vector for Study or Engraftment.

STAR Protoc 2020 Dec 25;1(3):100163. Epub 2020 Nov 25.

Princess Margaret Cancer Centre, University Health Network, Room 8-706, 101 College St., Toronto, ON M5G1L7, USA.

We describe a method to silence genes in primary acute myeloid leukemia cells by transducing them with shRNA in lentiviral vectors. The transduction of primary non-adherent cells is particularly challenging. The protocol will aid in performing such experiments and is particularly helpful to prepare cells for engraftment studies. Use of a special medium supplemented with cytokines preserves the viability of the leukemic stem cells and their ability to engraft the marrow of immune-deficient mice. For complete details on the use and execution of this protocol, please refer to Singh et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2020.100163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757357PMC
December 2020

Mitochondria regulate AML differentiation independent of oxidative phosphorylation and metabolism.

Mol Cell Oncol 2020 28;7(6):1815503. Epub 2020 Sep 28.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

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http://dx.doi.org/10.1080/23723556.2020.1815503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671065PMC
September 2020

E1 Enzymes as Therapeutic Targets in Cancer.

Pharmacol Rev 2021 01;73(1):1-58

Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (S.H.B., A.D.S.); Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada (S.H.B., A.D.S.); and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt (S.H.B.)

Post-translational modifications of cellular substrates with ubiquitin and ubiquitin-like proteins (UBLs), including ubiquitin, SUMOs, and neural precursor cell-expressed developmentally downregulated protein 8, play a central role in regulating many aspects of cell biology. The UBL conjugation cascade is initiated by a family of ATP-dependent enzymes termed E1 activating enzymes and executed by the downstream E2-conjugating enzymes and E3 ligases. Despite their druggability and their key position at the apex of the cascade, pharmacologic modulation of E1s with potent and selective drugs has remained elusive until 2009. Among the eight E1 enzymes identified so far, those initiating ubiquitylation (UBA1), SUMOylation (SAE), and neddylation (NAE) are the most characterized and are implicated in various aspects of cancer biology. To date, over 40 inhibitors have been reported to target UBA1, SAE, and NAE, including the NAE inhibitor pevonedistat, evaluated in more than 30 clinical trials. In this Review, we discuss E1 enzymes, the rationale for their therapeutic targeting in cancer, and their different inhibitors, with emphasis on the pharmacologic properties of adenosine sulfamates and their unique mechanism of action, termed substrate-assisted inhibition. Moreover, we highlight other less-characterized E1s-UBA6, UBA7, UBA4, UBA5, and autophagy-related protein 7-and the opportunities for targeting these enzymes in cancer. SIGNIFICANCE STATEMENT: The clinical successes of proteasome inhibitors in cancer therapy and the emerging resistance to these agents have prompted the exploration of other signaling nodes in the ubiquitin-proteasome system including E1 enzymes. Therefore, it is crucial to understand the biology of different E1 enzymes, their roles in cancer, and how to translate this knowledge into novel therapeutic strategies with potential implications in cancer treatment.
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http://dx.doi.org/10.1124/pharmrev.120.000053DOI Listing
January 2021

Mitochondrial ClpP serine protease-biological function and emerging target for cancer therapy.

Cell Death Dis 2020 10 9;11(10):841. Epub 2020 Oct 9.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Mitochondrial ClpP is a serine protease located in the mitochondrial matrix. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining normal metabolic function. Mitochondrial ClpP is a stable heptamer ring with peptidase activity that forms a multimeric complex with the ATP-dependent unfoldase ClpX (ClpXP) leading to proteolytic activity. Emerging evidence demonstrates that ClpXP is over-expressed in hematologic malignancies and solid tumors and is necessary for the viability of a subset of tumors. In addition, both inhibition and hyperactivation of ClpXP leads to impaired respiratory chain activity and causes cell death in cancer cells. Therefore, targeting mitochondrial ClpXP could be a novel therapeutic strategy for the treatment of malignancy. Here, we review the structure and function of mitochondrial ClpXP as well as strategies to target this enzyme complex as a novel therapeutic approach for malignancy.
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http://dx.doi.org/10.1038/s41419-020-03062-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547079PMC
October 2020

COVID-19: a pandemic experience that illuminates potential reforms to health research.

EMBO Mol Med 2020 11 19;12(11):e13278. Epub 2020 Oct 19.

Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

COVID-19 has halted research around the globe and forced researchers out of their laboratories. Non-emergency medical appointments were canceled. Ongoing clinical trials were challenged to create new modes of operation while public pressure mounted to find therapeutic options against COVID-19. Yet, the inability to conduct research during COVID-19 was overcome with cooperation, resource sharing, and compassion, which provides important lessons on how to improve health related research as we enter a new normal.
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http://dx.doi.org/10.15252/emmm.202013278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536940PMC
November 2020

Targeting neurolysin in acute myeloid leukemia.

Mol Cell Oncol 2020 23;7(4):1761243. Epub 2020 May 23.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

We recently identified the mitochondrial peptidase, neurolysin (NLN), as a top hit in an acute myeloid leukemia (AML) viability screen. Using chemical and genetic approaches, we demonstrated that loss of NLN disrupted respiratory chain supercomplex assembly and impaired oxidative metabolism in AML. Moreover, inhibition of NLN and reduced the growth of AML cells.
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http://dx.doi.org/10.1080/23723556.2020.1761243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469488PMC
May 2020

The role of mitochondrial proteases in leukemic cells and leukemic stem cells.

Stem Cells Transl Med 2020 12 5;9(12):1481-1487. Epub 2020 Aug 5.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

The biological function of most mitochondrial proteases has not been well characterized. Moreover, most of the available information on the normal function of these proteases has been derived from studies in model organisms. Recently, the mitochondrial proteases caseinolytic protease P (CLPP) and neurolysin (NLN) have been identified as therapeutic targets in acute myeloid leukemia (AML). Both proteases are overexpressed in approximately 40% of AML patients. Mechanistically, CLPP and NLN maintain the integrity of the mitochondrial respiratory chain: CLPP cleaves defective respiratory chain proteins, while NLN promotes the formation of respiratory chain supercomplexes. In this review, we highlight the functional consequences of inhibiting and activating mitochondrial proteases and discuss their potential as therapeutic targets in AML.
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http://dx.doi.org/10.1002/sctm.20-0142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695628PMC
December 2020

Cyclic AMP-hydrolyzing phosphodiesterase inhibitors potentiate statin-induced cancer cell death.

Mol Oncol 2020 10 25;14(10):2533-2545. Epub 2020 Aug 25.

Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

Dipyridamole, an antiplatelet drug, has been shown to synergize with statins to induce cancer cell-specific apoptosis. However, given the polypharmacology of dipyridamole, the mechanism by which it potentiates statin-induced apoptosis remains unclear. Here, we applied a pharmacological approach to identify the activity of dipyridamole specific to its synergistic anticancer interaction with statins. We evaluated compounds that phenocopy the individual activities of dipyridamole and assessed whether they could potentiate statin-induced cell death. Notably, we identified that a phosphodiesterase (PDE) inhibitor, cilostazol, and other compounds that increase intracellular cyclic adenosine monophosphate (cAMP) levels potentiate statin-induced apoptosis in acute myeloid leukemia and multiple myeloma cells. Additionally, we demonstrated that both dipyridamole and cilostazol further inhibit statin-induced activation of sterol regulatory element-binding protein 2, a known modulator of statin sensitivity, in a cAMP-independent manner. Taken together, our data support that PDE inhibitors such as dipyridamole and cilostazol can potentiate statin-induced apoptosis via a dual mechanism. Given that several PDE inhibitors are clinically approved for various indications, they are immediately available for testing in combination with statins for the treatment of hematological malignancies.
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http://dx.doi.org/10.1002/1878-0261.12775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530792PMC
October 2020

Targeting nuclear import and export in hematological malignancies.

Leukemia 2020 11 5;34(11):2875-2886. Epub 2020 Jul 5.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

The transport of proteins across the nuclear membrane is a highly regulated process, essential for the cell function. This transport is actively mediated by members of the karyopherin family, termed importins, or exportins, depending on the direction of transport. These proteins play an active part in tumorigenesis, through aberrant localization of their cargoes, which include oncogenes, tumor-suppressor genes and mediators of key signal transduction pathways. Overexpression of importins and exportins is reported in many malignancies, with implications in cell growth and viability, differentiation, drug resistance, and tumor microenvironment. Given their broad significance across tumors and pathways, much effort is being put to develop specific inhibitors as a novel anticancer therapeutics. Already, selinexor, a specific inhibitor of exportin-1 (XPO1), is approved for clinical use. This review will focus on the role of importins and exportins in hematological malignancies. We will discuss current preclinical and clinical data on importins and exportins, and demonstrate how our growing understanding of their functions has identified new therapeutic targets.
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http://dx.doi.org/10.1038/s41375-020-0958-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584478PMC
November 2020

Screening for Dental Infections Achieves 6-Fold Reduction in Dental Emergencies During Induction Chemotherapy for Acute Myeloid Leukemia.

JCO Oncol Pract 2020 11 1;16(11):e1397-e1405. Epub 2020 Jul 1.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Purpose: Patients with newly diagnosed acute myeloid leukemia (AML) are at risk of infection, including odontogenic infections, during induction chemotherapy. It is unknown whether clinical dental screening to diagnose and treat odontogenic disease in these patients can reduce the incidence of dental emergencies.

Methods: Between November 1, 2014, and December 31, 2016, we screened 147 patients with newly diagnosed AML before their admission for induction chemotherapy (n 147, "screened" group). The patients not screened acted as controls (n = 190, "unscreened" group), as did patients diagnosed with AML in the 26 months before the initiation of the screening program (n = 304, "prescreening" group). The number of patients in each group who presented for emergency dental assessment during admission for induction chemotherapy was determined by 2 independent reviewers.

Results: Among the 147 patients in the screened group, only 1 patient presented with an infectious odontogenic emergency (0.68% [95% CI, -0.64% to 1.98%]). In the unscreened group, 8 developed an infectious odontogenic emergency during induction chemotherapy (4.21% [95% CI, 1.37% to 7.15%]), a statistically significant difference ( = .046, = 0.05). A similar rate of infectious dental emergencies was observed in the prescreening group (4.28% [95% CI, 2.0% to 7.2%]).

Conclusion: Clinical dental screening before induction chemotherapy in patients with AML resulted in a 6-fold reduction in infectious dental emergencies during the induction period.
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http://dx.doi.org/10.1200/OP.20.00107DOI Listing
November 2020

Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal.

Cell Stem Cell 2020 06 15;26(6):926-937.e10. Epub 2020 May 15.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Electronic address:

Leukemic stem cells (LSCs) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins is folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal, and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone, and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-adenosylhomocysteine hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.
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http://dx.doi.org/10.1016/j.stem.2020.04.010DOI Listing
June 2020

Mitochondrial carrier homolog 2 is necessary for AML survival.

Blood 2020 07;136(1):81-92

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Through a clustered regularly insterspaced short palindromic repeats (CRISPR) screen to identify mitochondrial genes necessary for the growth of acute myeloid leukemia (AML) cells, we identified the mitochondrial outer membrane protein mitochondrial carrier homolog 2 (MTCH2). In AML, knockdown of MTCH2 decreased growth, reduced engraftment potential of stem cells, and induced differentiation. Inhibiting MTCH2 in AML cells increased nuclear pyruvate and pyruvate dehydrogenase (PDH), which induced histone acetylation and subsequently promoted the differentiation of AML cells. Thus, we have defined a new mechanism by which mitochondria and metabolism regulate AML stem cells and gene expression.
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http://dx.doi.org/10.1182/blood.2019000106DOI Listing
July 2020

The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability.

Sci Transl Med 2020 04;12(538)

Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.

Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function is unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition of NLN was selectively cytotoxic to AML cells and stem cells while sparing normal hematopoietic cells. Mechanistically, NLN interacted with the mitochondrial respiratory chain. Genetic and chemical inhibition of NLN impaired oxidative metabolism and disrupted the formation of respiratory chain supercomplexes (RCS). Furthermore, NLN interacted with the known RCS regulator, LETM1, and inhibition of NLN disrupted LETM1 complex formation. RCS were increased in patients with AML and positively correlated with NLN expression. These findings demonstrate that inhibiting RCS formation selectively targets AML cells and stem cells and highlights the therapeutic potential of pharmacologically targeting NLN in AML.
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http://dx.doi.org/10.1126/scitranslmed.aaz8264DOI Listing
April 2020

Measurable residual disease monitoring provides insufficient lead-time to prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia.

Haematologica 2021 01 1;106(1):56-63. Epub 2021 Jan 1.

Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

Core-binding factor acute myeloid leukemia is characterized by t(8;21) or inv(16) and the fusion proteins RUNX1-RUNX1T1 and CBFB-MYH11. International guidelines recommend monitoring for measurable residual disease every 3 months for 2 years after treatment. However, it is unknown if serial molecular monitoring can predict and prevent morphologic relapse. We conducted a retrospective single-center study of 114 patients in complete remission who underwent molecular monitoring with RT-qPCR of RUNX1-RUNX1T1 or CBFB-MYH11 transcripts every 3 months. Morphologic relapse was defined as re-emergence of >5% blasts and molecular relapse as ≥1 log increase in transcript level between 2 samples. Over a median follow-up time of 3.7 years (range 0.2-14.3), remission persisted in 71 (62.3%) patients but 43 (37.7%) developed molecular or morphologic relapse. Patients who achieved <3 log reduction in RUNX1-RUNX1T1 or CBFB-MYH11 transcripts at end of chemotherapy had a significantly higher risk of relapse compared to patients who achieved ≥3 log reduction (61.1% vs. 33.7%, p=0.004). The majority of relapses (74.4%, n=32) were not predicted by molecular monitoring and occurred rapidly with <100 days from molecular to morphologic relapse. Molecular monitoring enabled the detection of impending relapse and permitted pre-emptive intervention prior to morphologic relapse in only 11 (25.6%) patients. The current practice of molecular monitoring every 3 months provided insufficient lead-time to identify molecular relapses and prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia treated at our institution. Further research is necessary to determine the optimal monitoring strategies for these patients.
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http://dx.doi.org/10.3324/haematol.2019.235721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776265PMC
January 2021

Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response.

Sci Transl Med 2019 10;11(516)

Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.

Venetoclax is a specific B cell lymphoma 2 (BCL-2) inhibitor with promising activity against acute myeloid leukemia (AML), but its clinical efficacy as a single agent or in combination with hypomethylating agents (HMAs), such as azacitidine, is hampered by intrinsic and acquired resistance. Here, we performed a genome-wide CRISPR knockout screen and found that inactivation of genes involved in mitochondrial translation restored sensitivity to venetoclax in resistant AML cells. Pharmacologic inhibition of mitochondrial protein synthesis with antibiotics that target the ribosome, including tedizolid and doxycycline, effectively overcame venetoclax resistance. Mechanistic studies showed that both tedizolid and venetoclax suppressed mitochondrial respiration, with the latter demonstrating inhibitory activity against complex I [nicotinamide adenine dinucleotide plus hydrogen (NADH) dehydrogenase] of the electron transport chain (ETC). The drugs cooperated to activate a heightened integrated stress response (ISR), which, in turn, suppressed glycolytic capacity, resulting in adenosine triphosphate (ATP) depletion and subsequent cell death. Combination treatment with tedizolid and venetoclax was superior to either agent alone in reducing leukemic burden in mice engrafted with treatment-resistant human AML. The addition of tedizolid to azacitidine and venetoclax further enhanced the killing of resistant AML cells in vitro and in vivo. Our findings demonstrate that inhibition of mitochondrial translation is an effective approach to overcoming venetoclax resistance and provide a rationale for combining tedizolid, azacitidine, and venetoclax as a triplet therapy for AML.
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http://dx.doi.org/10.1126/scitranslmed.aax2863DOI Listing
October 2019

Tafazzin modulates cellular phospholipid composition to regulate AML stemness.

Mol Cell Oncol 2019 11;6(5):e1620051. Epub 2019 Jun 11.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Tafazzin is a mitochondrial enzyme necessary for the remodeling of the phospholipid cardiolipin. Seneviratne and Xu et al. demonstrated that Tafazzin-mediated phospholipid production regulates stemness in Acute Myeloid Leukemia (AML). Tafazzin influenced intracellular levels of phospholipids to control AML stemness. Thus, inhibiting mitochondrial phospholipid production could be a new therapeutic strategy for AML.
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http://dx.doi.org/10.1080/23723556.2019.1620051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736150PMC
June 2019

Phospholipid metabolism regulates AML growth and stemness.

Aging (Albany NY) 2019 06;11(12):3895-3897

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

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http://dx.doi.org/10.18632/aging.102055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628983PMC
June 2019

De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX.

J Med Chem 2019 07 26;62(13):6377-6390. Epub 2019 Jun 26.

Davenport Research Laboratories, Department of Chemistry , University of Toronto , 80 St. George Street , Toronto , Ontario M5S 3H6 , Canada.

Boronic acids have attracted the attention of synthetic and medicinal chemists due to boron's ability to modulate enzyme function. Recently, we demonstrated that boron-containing amphoteric building blocks facilitate the discovery of bioactive aminoboronic acids. Herein, we have augmented this capability with a de novo library design and a virtual screening platform modified for covalent ligands. This technique has allowed us to rapidly design and identify a series of α-aminoboronic acids as the first inhibitors of human ClpXP, which is responsible for the degradation of misfolded proteins.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00878DOI Listing
July 2019
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