Publications by authors named "Mark D Minden"

209 Publications

Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.

Cell Stem Cell 2021 Jul 12. Epub 2021 Jul 12.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, ON, Canada; Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, Canada. Electronic address:

Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.
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http://dx.doi.org/10.1016/j.stem.2021.06.004DOI Listing
July 2021

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

Blood 2021 Jul;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
July 2021

TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors.

Cancer Res 2021 Jul 2. Epub 2021 Jul 2.

Cambridge Stem Cell Institute/Haematology, University of Cambridge.

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK -mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2 - Wilms tumor 1 (WT1) binding ability were responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3761DOI Listing
July 2021

Structure-activity relationship of avocadyne.

Food Funct 2021 Jul 6;12(14):6323-6333. Epub 2021 Jun 6.

Department of Food Science, University of Guelph, 50 Stone Rd., Guelph, Ontario, CanadaN1G2W1.

Avocado consumption is associated with numerous health benefits. Avocadyne is a terminally unsaturated, 17-carbon long acetogenin found almost exclusively in avocados with noted anti-leukemia and anti-viral properties. In this study, specific structural features such as the terminal triple bond, odd number of carbons, and stereochemistry are shown to be critical to its ability to suppress mitochondrial fatty acid oxidation and impart selective activity in vitro and in vivo. Together, this is the first study to conduct a structure-activity analysis on avocadyne and outline the chemical moieties critical to fatty acid oxidation suppression.
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http://dx.doi.org/10.1039/d1fo00693bDOI Listing
July 2021

Recurrent deletions in clonal hematopoiesis are driven by microhomology-mediated end joining.

Nat Commun 2021 04 28;12(1):2455. Epub 2021 Apr 28.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.

The mutational mechanisms underlying recurrent deletions in clonal hematopoiesis are not entirely clear. In the current study we inspect the genomic regions around recurrent deletions in myeloid malignancies, and identify microhomology-based signatures in CALR, ASXL1 and SRSF2 loci. We demonstrate that these deletions are the result of double stand break repair by a PARP1 dependent microhomology-mediated end joining (MMEJ) pathway. Importantly, we provide evidence that these recurrent deletions originate in pre-leukemic stem cells. While DNA polymerase theta (POLQ) is considered a key component in MMEJ repair, we provide evidence that pre-leukemic MMEJ (preL-MMEJ) deletions can be generated in POLQ knockout cells. In contrast, aphidicolin (an inhibitor of replicative polymerases and replication) treatment resulted in a significant reduction in preL-MMEJ. Altogether, our data indicate an association between POLQ independent MMEJ and clonal hematopoiesis and elucidate mutational mechanisms involved in the very first steps of leukemia evolution.
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http://dx.doi.org/10.1038/s41467-021-22803-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080710PMC
April 2021

Loss of expression of both miR-15/16 loci in CML transition to blast crisis.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210;

Despite advances that have improved the treatment of chronic myeloid leukemia (CML) patients in chronic phase, the mechanisms of the transition from chronic phase CML to blast crisis (BC) are not fully understood. Considering the key role of miR-15/16 loci in the pathogenesis of myeloid and lymphocytic leukemia, here we aimed to correlate the expression of miR-15a/16 and miR-15b/16 to progression of CML from chronic phase to BC. We analyzed the expression of the two miR-15/16 clusters in 17 CML patients in chronic phase and 22 patients in BC and in 11 paired chronic phase and BC CML patients. BC CMLs show a significant reduction of the expression of miR-15a/-15b/16 compared to CMLs in chronic phase. Moreover, BC CMLs showed an overexpression of miR-15/16 direct targets such as Bmi-1, ROR1, and Bcl-2 compared to CMLs in chronic phase. This study highlights the loss of both miR-15/16 clusters as a potential oncogenic driver in the transition from chronic phase to BC in CML patients.
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http://dx.doi.org/10.1073/pnas.2101566118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980455PMC
March 2021

Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia.

Nat Cancer 2020 Nov 19;1(11):1113-1127. Epub 2020 Oct 19.

Institute for Cancer Genetics, Columbia University, New York, NY, USA.

Multi-agent combination chemotherapy can be curative in acute lymphoblastic leukemia (ALL). Still, patients with primary refractory disease or with relapsed leukemia have a very poor prognosis. Here we integrate an in-depth dissection of the mutational landscape across diagnostic and relapsed pediatric and adult ALL samples with genome-wide CRISPR screen analysis of gene-drug interactions across seven ALL chemotherapy drugs. By combining these analyses, we uncover diagnostic and relapse-specific mutational mechanisms as well as genetic drivers of chemoresistance. Functionally, our data identifies common and drug-specific pathways modulating chemotherapy response and underscores the effect of drug combinations in restricting the selection of resistance-driving genetic lesions. In addition, by identifying actionable targets for the reversal of chemotherapy resistance, these analyses open novel therapeutic opportunities for the treatment of relapse and refractory disease.
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http://dx.doi.org/10.1038/s43018-020-00124-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011577PMC
November 2020

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

Blood 2021 Mar 16. Epub 2021 Mar 16.

University of Toronto, Canada.

Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent, Azacytidine, achieves complete response with or without count recovery in approximately 70% of treatment-naïve 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 AML in vitro and in vivo. Venetoclax enhanced T cell effector function by increasing ROS 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 ROS generation and activated T cells. Collectively, this study demonstrates 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
March 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

Sphingosine-1-phosphate receptor 3 potentiates inflammatory programs in normal and leukemia stem cells to promote differentiation.

Blood Cancer Discov 2021 Jan 1;2(1):32-53. Epub 2020 Dec 1.

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

Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis, driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSC by activating stress myelopoiesis, such roles in LSC are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator which drives myeloid differentiation and activates inflammatory programs in both HSC and LSC. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across AML patient cohorts, each with distinct phenotypic and clinical properties. S1PR3 was high in LSC and blasts of mature myeloid samples with linkages to chemosensitivity, while S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.
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http://dx.doi.org/10.1158/2643-3230.BCD-20-0155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116590PMC
January 2021

Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.

Clin Cancer Res 2021 Apr 15;27(8):2190-2199. Epub 2021 Jan 15.

University of Virginia Cancer Center, Charlottesville, Virginia.

Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies.

Patients And Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR).

Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, = 35 and nivolumab combination, = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing.

Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3706DOI Listing
April 2021

Integration of intra-sample contextual error modeling for improved detection of somatic mutations from deep sequencing.

Sci Adv 2020 Dec 9;6(50). Epub 2020 Dec 9.

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

Sensitive mutation detection by next-generation sequencing is critical for early cancer detection, monitoring minimal/measurable residual disease (MRD), and guiding precision oncology. Nevertheless, because of artifacts introduced during library preparation and sequencing, the detection of low-frequency variants at high specificity is problematic. Here, we present Espresso, an error suppression method that considers local sequence features to accurately detect single-nucleotide variants (SNVs). Compared to other advanced error suppression techniques, Espresso consistently demonstrated lower numbers of false-positive mutation calls and greater sensitivity. We demonstrated Espresso's superior performance in detecting MRD in the peripheral blood of patients with acute myeloid leukemia (AML) throughout their treatment course. Furthermore, we showed that accurate mutation calling in a small number of informative genomic loci might provide a cost-efficient strategy for pragmatic risk prediction of AML development in healthy individuals. More broadly, we aim for Espresso to aid with accurate mutation detection in many other research and clinical settings.
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http://dx.doi.org/10.1126/sciadv.abe3722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725472PMC
December 2020

CRISPR screen identifies genes that sensitize AML cells to double-negative T-cell therapy.

Blood 2021 Apr;137(16):2171-2181

Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; and.

Acute myeloid leukemia (AML) remains a devastating disease in need of new therapies to improve patient survival. Targeted adoptive T-cell therapies have achieved impressive clinical outcomes in some B-cell leukemias and lymphomas but not in AML. Double-negative T cells (DNTs) effectively kill blast cells from the majority of AML patients and are now being tested in clinical trials. However, AML blasts obtained from ∼30% of patients show resistance to DNT-mediated cytotoxicity; the markers or mechanisms underlying this resistance have not been elucidated. Here, we used a targeted clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) screen to identify genes that cause susceptibility of AML cells to DNT therapy. Inactivation of the Spt-Ada-Gcn5-acetyltransferase (SAGA) deubiquitinating complex components sensitized AML cells to DNT-mediated cytotoxicity. In contrast, CD64 inactivation resulted in resistance to DNT-mediated cytotoxicity. Importantly, the level of CD64 expression correlated strongly with the sensitivity of AML cells to DNT treatment. Furthermore, the ectopic expression of CD64 overcame AML resistance to DNTs in vitro and in vivo. Altogether, our data demonstrate the utility of CRISPR/Cas9 screens to uncover mechanisms underlying the sensitivity to DNT therapy and suggest CD64 as a predictive marker for response in AML patients.
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http://dx.doi.org/10.1182/blood.2019004108DOI Listing
April 2021

Dasatinib response in acute myeloid leukemia is correlated with FLT3/ITD, PTPN11 mutations and a unique gene expression signature.

Haematologica 2020 12 1;105(12):2795-2804. Epub 2020 Dec 1.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.

Novel targeted therapies demonstrate improved survival in specific subgroups (defined by genetic variants) of acute myeloid leukemia (AML) patients, validating the paradigm of molecularly targeted therapy. However, identifying correlations between AML molecular attributes and effective therapies is challenging. Recent advances in high-throughput in vitro drug sensitivity screening applied to primary AML blasts were used to uncover such correlations; however, these methods cannot predict the response of leukemic stem cells (LSCs). Our study aimed to predict in vitro response to targeted therapies, based on molecular markers, with subsequent validation in LSCs. We performed ex vivo sensitivity screening to 46 drugs on 29 primary AML samples at diagnosis or relapse. Using unsupervised hierarchical clustering analysis we identified group with sensitivity to several tyrosine kinase inhibitors (TKIs), including the multi-TKI, dasatinib, and searched for correlations between dasatinib response, exome sequencing and gene expression from our dataset and from the Beat AML dataset. Unsupervised hierarchical clustering analysis of gene expression resulted in clustering of dasatinib responders and non-responders. In vitro response to dasatinib could be predicted based on gene expression (AUC=0.78). Furthermore, mutations in FLT3/ITD and PTPN11 were enriched in the dasatinib sensitive samples as opposed to mutations in TP53 which were enriched in resistant samples. Based on these results, we selected FLT3/ITD AML samples and injected them to NSG-SGM3 mice. Our results demonstrate that in a subgroup of FLT3/ITD AML (4 out of 9) dasatinib significantly inhibits LSC engraftment. In summary we show that dasatinib has an anti-leukemic effect both on bulk blasts and, more importantly, LSCs from a subset of AML patients that can be identified based on mutational and expression profiles. Our data provide a rational basis for clinical trials of dasatinib in a molecularly selected subset of AML patients.
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http://dx.doi.org/10.3324/haematol.2019.240705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726833PMC
December 2020

CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells.

Blood 2021 02;137(5):661-677

Bristol-Myers Squibb, San Diego, CA.

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).
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http://dx.doi.org/10.1182/blood.2020008676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215192PMC
February 2021

CD200 expression marks leukemia stem cells in human AML.

Blood Adv 2020 11;4(21):5402-5413

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

The leukemia stem cell (LSC) populations of acute myeloid leukemia (AML) exhibit phenotypic, genetic, and functional heterogeneity that contribute to therapy failure and relapse. Progress toward understanding the mechanistic basis for therapy resistance in LSCs has been hampered by difficulties in isolating cell fractions that enrich for the entire heterogeneous population of LSCs within individual AML samples. We previously reported that CD200 gene expression is upregulated in LSC-containing AML fractions. Here, we show that CD200 is present on a greater proportion of CD45dim blasts compared with more differentiated CD45high cells in AML patient samples. In 75% (49 of 65) of AML cases we examined, CD200 was expressed on ≥10% of CD45dim blasts; of these, CD200 identified LSCs within the blast population in 9 of 10 (90%) samples tested in xenotransplantation assays. CD200+ LSCs could be isolated from CD200+ normal HSCs with the use of additional markers. Notably, CD200 expression captured both CD34- and CD34+ LSCs within individual AML samples. Analysis of highly purified CD200+ LSC-containing fractions from NPM1-mutated AMLs, which are commonly CD34-, exhibited an enrichment of primitive gene expression signatures compared with unfractionated cells. Overall, our findings support CD200 as a novel LSC marker that is able to capture the entire LSC compartment from AML patient samples, including those with NPM1 mutation.
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http://dx.doi.org/10.1182/bloodadvances.2020001802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656934PMC
November 2020

Inflammatory Biomarkers, Hematopoietic Stem Cells, and Symptoms in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy.

JNCI Cancer Spectr 2020 Oct 8;4(5):pkaa037. Epub 2020 May 8.

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

Background: Fatigue and insomnia are common symptoms experienced by breast cancer patients undergoing adjuvant radiation therapy (RT), yet the underlying mechanisms of these symptoms are unclear. In particular, the roles of hematopoietic stem cells (HSCs) and inflammatory cytokines remain to be elucidated.

Methods: Breast cancer patients (n = 147) completed questionnaires to longitudinally assess symptoms before, during, and after adjuvant RT. Phlebotomies were performed prior to RT, at the second and fifth treatment fractions, end of treatment (EOT), and 1 month after completing RT, assessing for CD34, CD45, full hematology, and 17 inflammatory cytokines. The associations between symptoms and all biomarkers were evaluated. All statistical tests were 2-sided.

Results: General fatigue and insomnia worsened with RT, with peak levels observed at EOT, which remained statistically significant even after controlling for anxiety and depression ( < .05 for all). CD34, CD45, white blood cell, and lymphocyte counts decreased, with the lowest levels also observed at EOT ( < .001). Fatigue and insomnia were associated with changes in both interferon γ-induced protein 10 (IP-10) - ( = .03 and  = .01, respectively) and tumor necrosis factor receptor II (TNF-RII) ( = .02 and  = .006, respectively), while mental fatigue was associated with increased matrix metalloproteinases-2 (MMP-2) levels ( = .03). Patients who received prior chemotherapy demonstrated statistically significantly greater severity in all symptoms, with lower baseline HSC levels.

Conclusions: This is the first longitudinal study to examine linkages between symptoms, HSCs, and cytokines, demonstrating that fatigue and insomnia shared associations with increasing serum levels of IP-10 and TNF-RII, and mental fatigue was associated with increasing serum levels of MMP-2. Our findings highlight opportunities for further research into mechanisms and potential interventions for these symptoms.
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http://dx.doi.org/10.1093/jncics/pkaa037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583146PMC
October 2020

B cell acute lymphoblastic leukemia cells mediate RANK-RANKL-dependent bone destruction.

Sci Transl Med 2020 09;12(561)

Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.

Although most children survive B cell acute lymphoblastic leukemia (B-ALL), they frequently experience long-term, treatment-related health problems, including osteopenia and osteonecrosis. Because some children present with fractures at ALL diagnosis, we considered the possibility that leukemic B cells contribute directly to bone pathology. To identify potential mechanisms of B-ALL-driven bone destruction, we examined the ; ; triple mutant (TM) mice and ; double mutant (DM) mouse models of spontaneous B-ALL. In contrast to DM animals, leukemic TM mice displayed brittle bones, and the TM leukemic cells overexpressed , encoding receptor activator of nuclear factor κB ligand. RANKL is a key regulator of osteoclast differentiation and bone loss. Transfer of TM leukemic cells into immunodeficient recipient mice caused trabecular bone loss. To determine whether human B-ALL can exert similar effects, we evaluated primary human B-ALL blasts isolated at diagnosis for RANKL expression and their impact on bone pathology after their transplantation into NOD. /SzJ (NSG) recipient mice. Primary B-ALL cells conferred bone destruction evident in increased multinucleated osteoclasts, trabecular bone loss, destruction of the metaphyseal growth plate, and reduction in adipocyte mass in these patient-derived xenografts (PDXs). Treating PDX mice with the RANKL antagonist recombinant osteoprotegerin-Fc (rOPG-Fc) protected the bone from B-ALL-induced destruction even under conditions of heavy tumor burden. Our data demonstrate a critical role of the RANK-RANKL axis in causing B-ALL-mediated bone pathology and provide preclinical support for RANKL-targeted therapy trials to reduce acute and long-term bone destruction in these patients.
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http://dx.doi.org/10.1126/scitranslmed.aba5942DOI Listing
September 2020

Entospletinib in Combination with Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of and Expression.

Clin Cancer Res 2020 11 20;26(22):5852-5859. Epub 2020 Aug 20.

Winship Cancer Institute of Emory University, Atlanta, Georgia.

Purpose: Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to and overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML.

Patients And Methods: This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II.

Results: Fifty-three patients ( = 12, phase Ib and = 41, phase II) with previously untreated ( = 39) or secondary ( = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline and expression higher than the median had improved overall survival compared with patients with below median and expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed.

Conclusions: Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1064DOI Listing
November 2020

Acute myeloid leukemia with myelodysplasia-related changes diagnosed with multilineage dysplasia alone demonstrates a superior clinical outcome.

Hum Pathol 2020 10 13;104:117-126. Epub 2020 Aug 13.

Department of Laboratory Hematology, University Health Network, University of Toronto, Toronto, Canada. Electronic address:

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) generally confers poor prognosis; however, the clinical outcome remains heterogeneous. We sought to further stratify this subentity of AML by performing a retrospective analysis of 179 adult patients with AML-MRC diagnosed at our institution. Based on 2016 World Health Organization diagnostic criteria, 44 (25%) patients had multilineage dysplasia alone (AML-MRC-M), 74 (41%) had history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative disease (AML-MRC-H), and 61 (34%) had MDS-related cytogenetics (AML-MRC-C). AML-MRC-M and hematopoietic stem cell transplantation (HSCT) were associated with prolonged event-free survival (EFS) (P = 0.0051 and P < 0.0001, respectively) and overall survival (OS) (P = 0.0015 and P < 0.0001, respectively), whereas AML-MRC-C and age ≥60 years were associated with shorter EFS (P = 0.028 and P = 0.015, respectively) and OS (P = 0.021 and P = 0.013, respectively). Of note, NPM1 did not affect the patient's outcome. Multivariable analysis confirmed HSCT and AML-MRC-C as independent predictors for EFS (P < 0.0001 and P = 0.0342, respectively) and OS (P < 0.0001 and P = 0.0295, respectively). AML-MRC-M was an independent predictor for OS (P = 0.0449). When compared with a control group of 105 patients with normal karyotype AML not otherwise specified (NK-AML-NOS), patients with AML-MRC-M had similar EFS and OS (P = 0.99 and P = 0.91, respectively). However, AML-MRC-H and AML-MRC-C were associated with shorter EFS and OS (P = 0.0002 and P < 0.0001, respectively) than the same control group. In a subset of patients, next-generation sequencing analysis showed AML-MRC-M was associated with ASXL1 mutation compared with NK-AML (56% vs 6%). In conclusion, AML-MRC-M demonstrates a superior clinical outcome compared with the rest of the AML-MRC group. They have comparable outcomes to NK-AML-NOS, and these data suggest AML-MRC-M may be considered not to be classified in the same group as patients with other AML-MRC.
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http://dx.doi.org/10.1016/j.humpath.2020.08.003DOI Listing
October 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

Combination of FLT3-ITD Allelic Ratio, NPM1 Mutation, and Immunophenotypic Markers to Modulate Outcome Prediction in Patients with Normal Karyotype Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2020 11 23;26(11):1995-2000. Epub 2020 Jul 23.

Department of Laboratory Hematology, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

NPM1 mutation status and the allelic ratio (AR) of FLT3-internal tandem duplication (FLT3-ITD) are routinely tested for disease risk stratification in patients with normal karyotype (NK) acute myelogenous leukemia (AML); however, the predictive impact of immunophenotypic markers on different NPM1/FLT3 genotypes remains unclear. We performed a retrospective analysis of 423 patients with NK-AML subclassified into groups based on NPM1/FLT3 genotype. Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in 124 of 423 patients (29%) and was significantly associated with longer event-free survival (EFS) and overall survival (OS), except for patients with the favorable genotype, defined as mutated NPM1 (NPM1) combined with normal FLT3 status (FLT3-ITD) or FLT3-ITD AR <.5 (FLT3-ITD). A subset of AML patients bearing the favorable NPM1/FLT3-ITD genotype share similar outcomes with AML patients who have the intermediate FLT3/NPM1 genotype defined by normal NPM1 (NPM1) and FLT3-ITD. In these individuals, the lack of CD13 expression (CD13) was associated with shorter EFS (P = .041) and OS (P = .017). CD13 was an independent predictor for shorter OS (hazard ratio, 1.985; P = .028).
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http://dx.doi.org/10.1016/j.bbmt.2020.07.017DOI Listing
November 2020

Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia.

Sci Transl Med 2020 06;12(546)

John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham NG11 8NS, UK.

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This study dissected the complexity of the immune architecture of AML at high resolution and assessed its influence on therapeutic response. Using 442 primary bone marrow samples from three independent cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease classes and revealed critical differences in immune gene expression across age groups and molecular disease subtypes. Interferon (IFN)-γ-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles provides insights into the immuno-biology of AML and could inform the delivery of personalized immunotherapies to IFN-γ-dominant AML subtypes.
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http://dx.doi.org/10.1126/scitranslmed.aaz0463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427158PMC
June 2020

Repression of LKB1 by Sensitizes -Dependent Lymphoma to Biguanide Treatment.

Cell Rep Med 2020 May 19;1(2):100014. Epub 2020 May 19.

Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.

Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated expression in lymphoma cells promotes increased apoptosis to biguanide treatment and . This effect is driven by the -dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between expression and biguanide sensitivity in human cancer cells. Our results identify expression as a potential biomarker for biguanide sensitivity in malignancies.
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http://dx.doi.org/10.1016/j.xcrm.2020.100014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249503PMC
May 2020

Combined loss of function of two different loci of miR-15/16 drives the pathogenesis of acute myeloid leukemia.

Proc Natl Acad Sci U S A 2020 06 18;117(22):12332-12340. Epub 2020 May 18.

Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210;

Double knockout of the two miR-15/16 loci in mouse resulted in the development of acute myeloid leukemia (AML). This result suggested that, at least, a fraction of human AMLs could be due to a similar mechanism. We analyzed the role of the two miR-15/16 clusters in 93 myelodysplastic syndrome (MDS) patients divided in three subgroups: patients with MDS, patients with MDS before transforming into AML (MDS-T), and patients with AML evolving from MDS (MDS-AML). Then, we tested 139 AML cases and 14 different AML cell lines by assessing microRNA (miRNA) expression, target protein expression, genetic loss, and silencing. MDS-T and MDS-AML patients show a reduction of the expression of miR-15a/-15b/-16 compared to MDS patients. Each miRNA can significantly predict MDS and MDS-T groups. Then, 79% of primary AMLs show a reduced expression of miR-15a and/or miR-15b. The expression of miR-15a/-15b/-16 significantly stratified AML patients in two prognostic classes. Furthermore, 40% of AML cell lines showed a combined loss of the expression of miR-15a/-15b and overexpression of their direct/indirect targets. As potential mechanisms involved in the silencing of the two miR-15/16 loci, we identified a genetic loss of miR-15a and miR-15b and silencing of these two loci by methylation. We identified a potential driver oncogenic role in the loss of expression of both miR-15/16 clusters in the progression of MDS into AML and in AML pathogenesis. The stratification of AML patients, based on miR-15/16 expression, can lead to targeted and combination therapies for the treatment of this incurable disease.
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http://dx.doi.org/10.1073/pnas.2003597117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275703PMC
June 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
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