Targeting the Metabolic Regulator SIRT5 in Acute Myeloid Leukemia

Targeting the Metabolic Regulator SIRT5 in Acute Myeloid Leukemia


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 genotypedirected 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.


SIRT5 KD attenuates leukemia in a xenograft model  SIRT5 KD attenuates leukemia in a xenograft modelSIRT5 KD attenuates leukemia in a xenograft model.


SIRT5 as mitochondria illustration.SIRT5 as a mitochondria-localized enzyme belonging to a family of NAD+ dependent histone
deacetylases.
Schematic depicting metabolic consequences.Schematic depicting metabolic consequences of SIRT5 KD.
AML cells illustration.AML cells selectively dependent on SIRT5.
Cell lines graph.AML cells are slectively dependent on SIRT5

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 ?-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.

Deininger Laboratory Research Projects

Strategies to Target BCR-ABL1 Compound Mutants

Strategies to target BCR-ABL1 compound mutants in CML and Ph+ ALL

Targeting the Metabolic Regulator SIRT5 in Acute Myeloid Leukemia

Targeting the Metabolic Regulator SIRT5 in Acute Myeloid Leukemia

A Bioluminescent Assay for Direct Measurement of Sirtuin Activity in Cancer Cells

A Bioluminescent Assay for Direct Measurement of Sirtuin Activity in Cancer Cells

The Function of MS4A3 in Normal and Malignant Hematopoiesis

Function of MS4A3

 
Publications
Read a select list of Dr. Deiningers publications.
 
Team
Our laboratory includes research scientists, postdoctoral fellows, technicians, and undergraduate students. If you are interested in joining the team contact us.
 
Contact Us
Complete the contact us form to inquire about open lab positions or Dr. Deininger's research.
 
Versiti Blood Research Institute
Versiti Blood Research Institute investigators study blood disorders like hemophilia, blood cancers like leukemia, and other blood diseases.