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Principal Investigator: Michael W. Deininger
Organization: VERSITI BLOOD HEALTH, INC.
Fiscal Year: 2024
Award: $352,688
Funding agency: National Cancer Institute
PROJECT SUMMARY
TARGETING THE METABOLIC REGULATOR SIRT5 IN ACUTE MYELOID LEUKEMIA. AML is an aggressive
hematologic malignancy with <30% long-term survival. The current therapy standard, chemotherapy alone or
combined with allogeneic stem cell transplant, has not changed for decades. Despite initial responses, most
patients eventually relapse, suggesting persistence of leukemia initiating cells in protective niches. Inhibitors of
FLT3 or mutant isocitrate dehydrogenase 1/2 (IDH1/2) have expanded therapy options and validated the
paradigm of genotype-directed therapy. However, even with these new drugs, relapse is common and frequently
due to selection of subclones with resistance mutations in the drug target. Unlike FLT3 and IDH1/2 inhibitors,
the BCL2 inhibitor venetoclax is active in multiple AML genotypes, indicating that targeting shared vulnerabilities
in a genotype-agnostic manner can be effective. Unfortunately many venetoclax-induced responses are not
durable as leukemia cells adapt by activating alternative anti-apoptosis mechanisms or by reprogramming
mitochondrial metabolism. Microenvironmental protection, intra-tumoral heterogeneity and metabolic flexibility
limit the utility of current AML therapies. To identify new therapy targets in AML, we adapted an shRNA screen
for testing primary AML cells under bone marrow microenvironment-like conditions. We discovered that many
AML patient samples are highly dependent on SIRT5, while normal CD34+ cells are not. SIRT5 is a lysine
deacylase implicated in the regulation of energy metabolic pathways, including oxidative phosphorylation
(OXPHOS), fatty acid β-oxidation and glycolysis. SIRT5 knockdown (KD) reduces growth and increases
apoptosis in most AML cell lines, with consistent results upon disruption of SIRT5 using CRISPR/Cas9 or
NRD167, a novel cell-permeable SIRT5 inhibitor. Genetic absence of Sirt5 impairs in vitro transformation of
mouse hematopoietic cells by several myeloid oncogenes, including MLL-AF9, and attenuates leukemogenesis
in vivo. At a biochemical level, SIRT5 KD or inhibition with NRD167 is associated with reduced OXPHOS,
reduced glutathione levels and increased mitochondrial superoxide, suggesting that AML cells depend on SIRT5
to maintain redox homeostasis. Sirt5-/- mice are viable with minor metabolic abnormalities, suggesting that in
vivo inhibition of SIRT5 would be tolerated. We hypothesize that SIRT5 is a therapy target in AML and will test
this in three Specific Aims: (1) Identify and validate SIRT5-regulated metabolic pathways in normal and
AML stem and progenitor cells. (2) Identify biomarkers of sensitivity to SIRT5 inhibition in primary AML
cells. (3) Identify a potent, selective, and bioavailable SIRT5 inhibitor, starting from the NRD167 tool
compound. Our work will rigorously test whether SIRT5 is a therapy target in AML, clarify the mechanisms
underlying SIRT5 dependence, and identify potent and selective SIRT5 inhibitors for future clinical development.
Terms: <AML - Acute Myeloid Leukemia><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Allogenic><Apoptosis><Apoptosis Pathway><Attenuated><Autoregulation><B cell lymphoma 2><B-Cell CLL/Lymphoma 2 Gene><B-cell lymphoma/leukemia-2><BCL2><BCL2 gene><Bcl-2><Bioavailability><Biochemical><Biological Availability><Biology><Blood Precursor Cell><Blood leukocyte><Bone Marrow><Bone Marrow Reticuloendothelial System><CD34><CD34 gene><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Genes><Cancer-Promoting Gene><Cas nuclease technology><Catabolism><Cell Body><Cell Death><Cell Line><Cell Survival><Cell Viability><CellLine><Cells><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Data><Dependence><Development><Drug Targeting><Drug Therapy><Drugs><Energy Expenditure><Energy Metabolism><Enzyme Gene><Enzymes><Equilibrium><Exhibits><Expression Signature><FLK2><FLT3><FLT3 gene><FLT3 inhibitor><FMS-like tyrosine kinase 3><Fatty Acids><Fms-Related Tyrosine Kinase 3><Future><Gene Expression Profile><Generalized Growth><Genes><Genetic><Genotype><Gln><Glutamine><Glycolysis><Granulocytic Leukemia><Growth><HPCA1><HSC subsets><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic><Hematopoietic Cancer><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Progenitor Cells><Hematopoietic Stem Cell subsets><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Hematopoietic progenitor subsets><Hematopoietic stem cells><Homeostasis><Impairment><In Vitro><In complete remission><Intermediary Metabolism><Intratumoral heterogeneity><Isocitrate Dehydrogenase><Knock-out><Knockout><L-Glutamine><L-Lysine><Lead><Leukemic Cell><Leukemic Hematopoietic Stem Cell><Leukemic progenitor and stem cell><Leukocytes><Leukocytes Reticuloendothelial System><Lysine><MLL-AF9><MLL/AF9 AML><Malignant><Malignant - descriptor><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Hematopoietic Neoplasm><Marrow leukocyte><Medication><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolic stress><Metabolism><Mice><Mice Mammals><Minor><Mitochondria><Murine><Mus><Myelocytic Leukemia><Myelogenous><Myelogenous Leukemia><Myeloid><Myeloid Disease><Myeloid Leukemia><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><Non-Lymphoblastic Leukemia><Non-Lymphocytic Leukemia><Nonlymphoblastic Leukemia><Nonlymphocytic Leukemia><Oncogenes><Organ><Oxidation-Reduction><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Patients><Pb element><Permeability><Pharmaceutical Preparations><Pharmacotherapy><Phenotype><Physiologic Availability><Physiological Homeostasis><Progenitor Cell Transplantation><Progenitor Cells><Prognosis><Programmed Cell Death><Proliferating><Q Levoglutamide><Q. Levoglutamide><RNA Seq><RNA sequencing><RNAseq><Reagent><Redox><Reduced Glutathione><Regulation><Relapse><Resistance development><Resistant development><Role><STK-1 kinase><STK1><Sampling><Silent Mating Type Information Regulator 2-like Proteins><Sir2-like Proteins><Sirtuins><Solid Neoplasm><Solid Tumor><Somatic Mutation><Stem Cell Transplantation><Stem Cell Tyrosine Kinase 1><Stem cell transplant><Strains Cell Lines><Stress><Superoxide Anion><Superoxide Radical><Superoxides><Testing><Therapeutic><Tissue Growth><Transforming Genes><Validation><White Blood Cells><White Cell><Work><acute granulocytic leukemia><acute granulocytic leukemia cell><acute myeloblastic leukemia cell><acute myelocytic leukemia cell><acute myelogenous leukemia cell><acute myeloid leukemia><acute myeloid leukemia cell><acute nonlymphocytic leukemia cell><attenuate><attenuates><balance><balance function><bcl-2 Genes><biomarker identification><blood cancer><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><branched chain amino acid aminotransferase><branched-chain L-amino-acid aminotransferase><branched-chain aminotransferases><branched-chain-amino-acid transaminase><cancer cell><cancer of blood><cancer of the blood><ced9 homolog><chemotherapy><clinical development><complete response><cultured cell line><developing resistance><developmental><drug treatment><drug/agent><exome sequencing><exome-seq><experience><fetal liver kinase-2><fetal liver kinase-3><flexibility><flexible><gene expression pattern><gene expression signature><glutamate-branched chain amino acid transaminase><heavy metal Pb><heavy metal lead><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><heterogeneity in tumors><identification of biomarkers><identification of new biomarkers><in vivo><inhibitor><intra-tumoral heterogeneity><intratumor heterogeneity><knock-down><knockdown><leukemia initiating cell><leukemia treatment><leukemic hematopoietic progenitor><leukemic hematopoietic stem and progenitor cells><leukemic progenitor><leukemic stem cell><leukemic therapy><leukemogenesis><marker identification><meter><mitochondrial><mitochondrial metabolism><mouse model><murine model><mutant><myeloid granulocytic leukemia><myeloproliferative neoplasm><myelosis><nano-molar><nanomolar><necrocytosis><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ontogeny><oxidation><oxidation reduction reaction><progenitor transplantation><relapse patients><resistance mutation><resistant mutation><response><scaffold><scaffolding><segregation><shRNA><short hairpin RNA><small hairpin RNA><social role><somatic variant><stable isotope><stem and progenitor cell transplantations><stem cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tool><transaminase B><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><tumor heterogeneity><validations><white blood cell><white blood corpuscle>