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1.
J Am Soc Nephrol ; 33(6): 1154-1171, 2022 06.
Article in English | MEDLINE | ID: mdl-35523579

ABSTRACT

BACKGROUND: The pathophysiology of AKI during tumor lysis syndrome (TLS) is not well understood due to the paucity of data. We aimed to decipher crystal-dependent and crystal-independent mechanisms of TLS-induced AKI. METHODS: Crystalluria, plasma cytokine levels, and extracellular histones levels were measured in two cohorts of patients with TLS. We developed a model of TLS in syngeneic mice with acute myeloid leukemia, and analyzed ultrastructural changes in kidneys and endothelial permeability using intravital confocal microscopy. In parallel, we studied the endothelial toxicity of extracellular histones in vitro. RESULTS: The study provides the first evidence that previously described crystal-dependent mechanisms are insufficient to explain TLS-induced AKI. Extracellular histones that are released in huge amounts during TLS caused profound endothelial alterations in the mouse model. The mechanisms of histone-mediated damage implicates endothelial cell activation mediated by Toll-like receptor 4. Heparin inhibits extracellular histones and mitigates endothelial dysfunction during TLS. CONCLUSION: This study sheds new light on the pathophysiology of TLS-induced AKI and suggests that extracellular histones may constitute a novel target for therapeutic intervention in TLS when endothelial dysfunction occurs.


Subject(s)
Acute Kidney Injury , Tumor Lysis Syndrome , Acute Kidney Injury/therapy , Animals , Endothelium , Histones , Humans , Kidney , Mice , Tumor Lysis Syndrome/drug therapy , Tumor Lysis Syndrome/etiology
2.
Blood ; 136(4): 387-400, 2020 07 23.
Article in English | MEDLINE | ID: mdl-32344427

ABSTRACT

Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins deregulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins, we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A, and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely attenuated NUP98-fusion-driven leukemogenesis, and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions.


Subject(s)
Cyclin-Dependent Kinase 6/metabolism , Drug Delivery Systems , Leukemia, Myeloid, Acute/metabolism , Nuclear Pore Complex Proteins/metabolism , Oncogene Proteins, Fusion/metabolism , Animals , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/genetics , Gene Expression Profiling , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mice , Nuclear Pore Complex Proteins/genetics , Oncogene Proteins, Fusion/genetics
3.
4.
Blood ; 129(5): 547-552, 2017 02 02.
Article in English | MEDLINE | ID: mdl-27956388

ABSTRACT

Autophagy is a lysosomal pathway involved in degradation of intracellular material. It appears as an adaptation mechanism that is essential for cellular homeostasis in response to various stress conditions. Over the past decade, many studies have linked alteration of autophagy with cancer initiation and progression, autoimmune, inflammatory, metabolic, and degenerative diseases. This review highlights recent findings on the impact of autophagy on leukemic transformation of normal hematopoietic stem cells and summarizes its role on leukemic cell response to chemotherapy.


Subject(s)
Autophagy , Cell Transformation, Neoplastic/pathology , Hematopoietic Stem Cells/pathology , Leukemia/pathology , Animals , Antinematodal Agents/pharmacology , Antinematodal Agents/therapeutic use , Autophagy/drug effects , Carcinogenesis/drug effects , Carcinogenesis/pathology , Cell Transformation, Neoplastic/drug effects , Drug Resistance, Neoplasm , Hematopoietic Stem Cells/drug effects , Humans , Leukemia/drug therapy
6.
Blood ; 123(5): 734-42, 2014 Jan 30.
Article in English | MEDLINE | ID: mdl-24282218

ABSTRACT

Blasts from approximately one-third of patients with acute myeloid leukemia (AML) harbor activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase that confer a poor prognosis. The Mucin 1-C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in AML blasts and stem cells; however, there is no known interaction between MUC1-C and FLT3. The present studies demonstrate that MUC1-C associates with wild-type and mutant FLT3 in AML cells. Targeting MUC1-C with the cell-penetrating peptide inhibitor GO-203 disrupts MUC1-C/FLT3 complexes and downregulates FLT3 activation. GO-203 treatment of AML cells was also associated with inhibition of the FLT3 downstream effectors AKT, extracellular signal-regulated kinase, and STAT5. The results further show that AML cells with FLT3-activating mutations and resistant to the FLT3 inhibitor midostaurin/PKC412 are sensitive to GO-203-induced growth arrest and death. Moreover, GO-203 increases sensitivity of mutant FLT3 AML cells to FLT3 inhibitor treatment. These results indicate that MUC1-C contributes to FLT3 activation in AML cells and that targeting MUC1-C inhibits the FLT3 signaling pathway. Our findings support the development of MUC1-C inhibitors alone and in combination with agents that target FLT3 for the treatment of wild-type and mutant FLT3 AML.


Subject(s)
Leukemia, Myeloid, Acute/metabolism , Mucin-1/metabolism , Oncogene Proteins/metabolism , fms-Like Tyrosine Kinase 3/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Activation/drug effects , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mice , Mice, Inbred BALB C , Peptides/pharmacology , Peptides/therapeutic use , Signal Transduction/drug effects , Tumor Cells, Cultured , fms-Like Tyrosine Kinase 3/genetics
7.
NAR Genom Bioinform ; 6(2): lqae059, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38800827

ABSTRACT

Recent advancements in shRNA and Cas protein technologies have enabled functional screening methods targeting genes or non-coding regions using single or pooled shRNA and sgRNA. CRISPR-based systems have also been developed for modulating DNA accessibility, resulting in CRISPR-mediated interference (CRISPRi) or activation (CRISPRa) of targeted genes or genomic DNA elements. However, there is still a lack of software tools for integrating diverse array of functional genomics screening outputs that could offer a cohesive framework for comprehensive data integration. Here, we developed PitViper, a flexible and interactive open-source software designed to fill this gap, providing reliable results for the type of elements being screened. It is an end-to-end automated and reproducible bioinformatics pipeline integrating gold-standard methods for functional screening analysis. Our sensitivity analyses demonstrate that PitViper is a useful tool for identifying potential super-enhancer liabilities in a leukemia cell line through genome-wide CRISPRi-based screening. It offers a robust, flexible, and interactive solution for integrating data analysis and reanalysis from functional screening methods, making it a valuable resource for researchers in the field.

8.
Mol Cancer Ther ; 23(8): 1159-1175, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38641421

ABSTRACT

Innovative strategies for enhancing efficacy and overcoming drug resistance in hematologic cancers, such as using antibody-drug conjugates (ADC), have shifted the paradigm of conventional care by delivering promising outcomes in cancer therapies with a significant reduction in the risk of relapse. Transferrin receptor (TfR1), cluster of differentiation 71 (CD71), is known to be overexpressed in malignant cells and considered a potent antitumor target. Therefore, we developed an anti-CD71 ADC, INA03, a humanized antibody conjugated to monomethyl auristatin E through a 3-arylpropiolonitrile-valine-citrulline linker. In this study, we investigated the potency and safety of INA03, in competition with Transferrin (Tf), the CD71's natural ligand, as a novel strategy to specifically target highly proliferative cells. The high expression of CD71 was confirmed on different leukemic cell lines, allowing INA03 to bind efficiently. Subsequently, INA03 rapidly internalizes into lysosomal compartments, in which its cytotoxic drug is released following cathepsin B cleavage. Downregulation of CD71 expression using shRNA highlighted that INA03-induced cell death was dependent on CD71 density at the cell surface. INA03 intravenous treatment in acute leukemia mouse models significantly reduced tumor burden, increased mouse survival, and showed no residual disease compared with conventional chemotherapies. Because INA03 competes with human Tf, a double knock-in (human CD71/human Tf) competent mouse model was generated to mimic human pharmacokinetics and pharmacodynamics. INA03 administration in human CD71/hTf mice did not reveal any improper toxicities, even at high doses. Hence, these data demonstrate the promising preclinical efficacy and safety of INA03 and support its development as a novel acute leukemia treatment. Significance: The Tf receptor is believed to be undruggable because of its ubiquitous expression. By entering into competition with its cognate ligand, the Tf and INA03 ADC can safely achieve potency.


Subject(s)
Antigens, CD , Immunoconjugates , Receptors, Transferrin , Transferrin , Humans , Animals , Mice , Receptors, Transferrin/metabolism , Receptors, Transferrin/antagonists & inhibitors , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Antigens, CD/metabolism , Transferrin/metabolism , Xenograft Model Antitumor Assays , Cell Line, Tumor , Leukemia/drug therapy , Leukemia/pathology , Female
9.
Nat Cancer ; 5(7): 1082-1101, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38816660

ABSTRACT

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.


Subject(s)
Class Ib Phosphatidylinositol 3-Kinase , Leukemia, Myeloid, Acute , Proto-Oncogene Proteins c-akt , Signal Transduction , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/genetics , Humans , Animals , Mice , Signal Transduction/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Class Ib Phosphatidylinositol 3-Kinase/genetics , Cell Line, Tumor , Xenograft Model Antitumor Assays , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Proteolysis/drug effects , Female , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use
10.
bioRxiv ; 2023 Jan 19.
Article in English | MEDLINE | ID: mdl-36711936

ABSTRACT

Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets EGFR-mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant, EGFR-mutant NSCLC cells.

11.
Cancer Discov ; 12(7): 1617-1619, 2022 07 06.
Article in English | MEDLINE | ID: mdl-35791696

ABSTRACT

Ellegast and colleagues show that monocytic acute myeloid leukemias (AML), enriched in inflammatory and immune gene sets, exploit a transcriptional repressor-namely, IRF2BP2-to mitigate their cell-intrinsic inflammatory output and ensure their maintenance. IRF2BP2 ablation results in heightened inflammatory signals that reach a set point that triggers apoptotic AML cell death in an NF-κB-IL1ß-dependent manner. The study identifies IRF2BP2 as a cell-intrinsic vulnerability with potential therapeutic significance in monocytic AML. See related article by Ellegast et al., p. 1760 (6).


Subject(s)
Leukemia, Myeloid, Acute , Humans , Inflammation , Leukemia, Myeloid, Acute/genetics , Monocytes
12.
Blood Rev ; 54: 100932, 2022 07.
Article in English | MEDLINE | ID: mdl-35148910

ABSTRACT

The role of the vascular microenvironment is increasingly studied in acute myeloid leukaemia (AML). Complex interactions between endothelial cells (ECs) and pre-leukaemic cells may contribute to the clonal evolution of pre-leukaemic stem cells in the bone marrow niche and to the proliferation, survival and chemoresistance of leukaemic cells. Through the expression of different adhesion molecules, ECs play a key role in the development of specific acute complications of AML, including leukostasis, acute respiratory failure, acute kidney injury or neurological complications. Moreover, in newly diagnosed patients, leukaemic cells promote endothelial activation and subsequent disseminated intravascular coagulation. Mechanisms of this bi-directional dialogue between leukaemic cells and ECs will reveal possible therapeutic targets to be explored to improve the survival of AML patients.


Subject(s)
Endothelial Cells , Leukemia, Myeloid, Acute , Bone Marrow/metabolism , Bone Marrow Cells/metabolism , Clonal Evolution , Endothelial Cells/metabolism , Humans , Leukemia, Myeloid, Acute/metabolism , Tumor Microenvironment/physiology
13.
Cell Rep ; 40(6): 111177, 2022 08 09.
Article in English | MEDLINE | ID: mdl-35947955

ABSTRACT

Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoproteomics in primary AML patient samples and cell lines. Functional phosphosite scoring reveals that p53 function is required for selinexor sensitivity consistent with enhanced efficacy of selinexor in combination with the MDM2 inhibitor nutlin-3a. Moreover, combining selinexor with the AKT inhibitor MK-2206 overcomes dysregulated AKT-FOXO3 signaling in resistant cells, resulting in synergistic anti-proliferative effects. Using high-throughput spatial proteomics to profile subcellular compartments, we measure global proteome and phospho-proteome dynamics, providing direct evidence of nuclear translocation of FOXO3 upon combination treatment. Our data demonstrate the potential of phosphoproteomics and functional phosphorylation site scoring to successfully pinpoint key targetable signaling hubs for rational drug combinations.


Subject(s)
Leukemia, Myeloid, Acute , Tumor Suppressor Protein p53 , Apoptosis , Cell Line, Tumor , Drug Resistance, Neoplasm , Humans , Hydrazines , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Proteome/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Triazoles , Tumor Suppressor Protein p53/metabolism
14.
Leukemia ; 36(2): 348-360, 2022 02.
Article in English | MEDLINE | ID: mdl-34341479

ABSTRACT

Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers.


Subject(s)
CRISPR-Cas Systems , Drug Resistance, Neoplasm/drug effects , Enzyme Inhibitors/pharmacology , Folic Acid/metabolism , Glycine Hydroxymethyltransferase/antagonists & inhibitors , Methotrexate/pharmacology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Animals , Antimetabolites, Antineoplastic/pharmacology , Apoptosis , Cell Cycle , Cell Proliferation , Female , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
15.
Sci Adv ; 8(6): eabg9455, 2022 Feb 11.
Article in English | MEDLINE | ID: mdl-35138899

ABSTRACT

Super Enhancers (SEs) are clusters of regulatory elements associated with cell identity and disease. However, whether these elements are induced by oncogenes and can regulate gene modules cooperating for cancer cell transformation or maintenance remains elusive. To address this question, we conducted a genome-wide CRISPRi-based screening of SEs in ETO2-GLIS2+ acute megakaryoblastic leukemia. This approach revealed SEs essential for leukemic cell growth and survival that are induced by ETO2-GLIS2 expression. In particular, we identified a de novo SE specific of this leukemia subtype and regulating expression of tyrosine kinase-associated receptors KIT and PDGFRA. Combined expression of these two receptors was required for leukemic cell growth, and CRISPRi-mediated inhibition of this SE or treatment with tyrosine kinase inhibitors impaired progression of leukemia in vivo in patient-derived xenografts experiments. Our results show that fusion oncogenes, such as ETO2-GLIS2, can induce activation of SEs regulating essential gene modules synergizing for leukemia progression.

16.
Blood Cancer J ; 12(6): 95, 2022 06 24.
Article in English | MEDLINE | ID: mdl-35750691

ABSTRACT

Functional precision medicine in AML often relies on short-term in vitro drug sensitivity screening (DSS) of primary patient cells in standard culture conditions. We designed a niche-like DSS assay combining physiologic hypoxia (O2 3%) and mesenchymal stromal cell (MSC) co-culture with multiparameter flow cytometry to enumerate lymphocytes and differentiating (CD11/CD14/CD15+) or leukemic stem cell (LSC)-enriched (GPR56+) cells within the leukemic bulk. After functional validation of GPR56 expression as a surrogate for LSC enrichment, the assay identified three patterns of response, including cytotoxicity on blasts sparing LSCs, induction of differentiation, and selective impairment of LSCs. We refined our niche-like culture by including plasma-like amino-acid and cytokine concentrations identified by targeted metabolomics and proteomics of primary AML bone marrow plasma samples. Systematic interrogation revealed distinct contributions of each niche-like component to leukemic outgrowth and drug response. Short-term niche-like culture preserved clonal architecture and transcriptional states of primary leukemic cells. In a cohort of 45 AML samples enriched for NPM1c AML, the niche-like multiparametric assay could predict morphologically (p = 0.02) and molecular (NPM1c MRD, p = 0.04) response to anthracycline-cytarabine induction chemotherapy. In this cohort, a 23-drug screen nominated ruxolitinib as a sensitizer to anthracycline-cytarabine. This finding was validated in an NPM1c PDX model.


Subject(s)
Leukemia, Myeloid, Acute , Mesenchymal Stem Cells , Anthracyclines/metabolism , Anthracyclines/therapeutic use , Cytarabine/therapeutic use , Drug Evaluation, Preclinical , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mesenchymal Stem Cells/metabolism , Neoplastic Stem Cells/metabolism
17.
Nat Cancer ; 3(7): 837-851, 2022 07.
Article in English | MEDLINE | ID: mdl-35668193

ABSTRACT

Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.


Subject(s)
Leukemia, Myeloid, Acute , Proto-Oncogene Proteins c-akt , Animals , Antineoplastic Combined Chemotherapy Protocols , Karyopherins/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Mice , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Purinergic P2Y2/metabolism , United States , Exportin 1 Protein
18.
Leukemia ; 36(6): 1585-1595, 2022 06.
Article in English | MEDLINE | ID: mdl-35474100

ABSTRACT

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.


Subject(s)
Cystine , Leukemia, Myeloid, Acute , Cell Line, Tumor , Cysteine , Cystine/metabolism , Cystine/therapeutic use , Daunorubicin/pharmacology , Daunorubicin/therapeutic use , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Nuclear Proteins , Sulfasalazine/pharmacology , Sulfasalazine/therapeutic use
19.
Magn Reson Chem ; 49(8): 533-6, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21761452

ABSTRACT

Citharoxazole (1), a new batzelline derivative featuring a benzoxazole moiety, was isolated from the Mediterranean deep-sea sponge Latrunculia (Biannulata) citharistae Vacelet, 1969, together with the known batzelline C (2). This is the first chemical study of a Mediterranean Latrunculia species and the benzoxazole moiety is unprecedented for this family of marine natural products. The structure was mainly elucidated by the interpretation of NMR spectra and especially HMBC correlations.


Subject(s)
Benzoxazoles/chemistry , Porifera/chemistry , Animals , Benzoxazoles/isolation & purification , Magnetic Resonance Spectroscopy , Mediterranean Sea , Molecular Structure
20.
Sci Transl Med ; 13(587)2021 03 31.
Article in English | MEDLINE | ID: mdl-33790022

ABSTRACT

The development and survival of cancer cells require adaptive mechanisms to stress. Such adaptations can confer intrinsic vulnerabilities, enabling the selective targeting of cancer cells. Through a pooled in vivo short hairpin RNA (shRNA) screen, we identified the adenosine triphosphatase associated with diverse cellular activities (AAA-ATPase) valosin-containing protein (VCP) as a top stress-related vulnerability in acute myeloid leukemia (AML). We established that AML was the most responsive disease to chemical inhibition of VCP across a panel of 16 cancer types. The sensitivity to VCP inhibition of human AML cell lines, primary patient samples, and syngeneic and xenograft mouse models of AML was validated using VCP-directed shRNAs, overexpression of a dominant-negative VCP mutant, and chemical inhibition. By combining mass spectrometry-based analysis of the VCP interactome and phospho-signaling studies, we determined that VCP is important for ataxia telangiectasia mutated (ATM) kinase activation and subsequent DNA repair through homologous recombination in AML. A second-generation VCP inhibitor, CB-5339, was then developed and characterized. Efficacy and safety of CB-5339 were validated in multiple AML models, including syngeneic and patient-derived xenograft murine models. We further demonstrated that combining DNA-damaging agents, such as anthracyclines, with CB-5339 treatment synergizes to impair leukemic growth in an MLL-AF9-driven AML murine model. These studies support the clinical testing of CB-5339 as a single agent or in combination with standard-of-care DNA-damaging chemotherapy for the treatment of AML.


Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Adenosine Triphosphatases/metabolism , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , DNA Repair , Humans , Leukemia, Myeloid, Acute/drug therapy , Mice , Valosin Containing Protein
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