Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Mussai, Francis; Egan, Sharon A.; Higginbotham-Jones, Joseph; Perry, Tracey; Beggs, Andrew D; Odintsova, Elena; Loke, Justin; Pratt, Guy; U, Kin Pong; Lo, Anthony W.I.; Ng, Margaret H.L.; Kearns, Pamela; Cheng, Paul; Santo, Carmela De

doi:10.1182/blood-2014-09-600643

Cited by 132 publications

(147 citation statements)

References 62 publications

(74 reference statements)

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“…In healthy cells, arginine can be produced by the ornithine-citrulline-arginine cycle. However, recent investigations identified that the majority of blasts from patients with AML are deficient in enzymes specialized in promoting this cycle and are therefore strongly reliant on extracellular arginine availability 26,27 . This study suggests that a constitutive blockade of the ornithine-citrulline-arginine cycle would preferentially redirect transported arginine through other arginine-dependent metabolic pathways such as the creatine pathway.…”

Section: Discussionmentioning

confidence: 99%

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

Fenouille

Bassil

Ben-Sahra

et al. 2017

Nat Med

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Expression of the EVI1 proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A pooled shRNA screen identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as a metabolic dependency in EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted cell cycle arrest and apoptosis of human EVI1-positive AML cells, and prolonged survival in human orthotopic and mouse primary AML models. CKMT1 inhibition alters mitochondrial respiration and ATP production, an effect that is abrogated by phospho-creatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.

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Section: Discussionmentioning

confidence: 99%

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

Fenouille

Bassil

Ben-Sahra

et al. 2017

Nat Med

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“…Beyond the Warburg effect, other effects, especially fatty acid oxidation ( FAO ) (Carracedo et al, 2013), also show important roles in the cancer pathogenesis. Series reports of therapeutic applications for metabolic signatures have appeared for AML, including a distinct glucose metabolism signature proved as a prognostic biomarker (Chen et al, 2014), glutamine uptake (Willems et al, 2013) and arginine dependence (Mussai et al, 2015) reported as novel therapeutic targets. Particular concerns were paid on FAO , an original article and editorial discussed function blocking of FAO with CPT1A 's inhibitor (ST1326) and its inherent mechanisms for anti-leukemia treatment (Ricciardi et al, 2015, Samudio and Konopleva, 2015).…”

Section: Introductionmentioning

confidence: 99%

High Expression of CPT1A Predicts Adverse Outcomes: A Potential Therapeutic Target for Acute Myeloid Leukemia

Shi

Jia

et al. 2016

EBioMedicine

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Carnitine palmitoyl transferase 1A (CPT1A) protein catalyzes the rate-limiting step of Fatty-acid oxidation (FAO) pathway, which can promote cell proliferation and suppress apoptosis. Targeting CPT1A has shown remarkable anti-leukemia activity. But, its prognostic value remains unclear in Acute Myeloid Leukemia (AML). In two independent cohorts of cytogenetically normal AML (CN-AML) patients, compared to low expression of CPT1A (CPT1Alow), high expression of CPT1A (CPT1Ahigh) was significantly associated with adverse outcomes, which was also shown in European Leukemia Network (ELN) Intermediate-I category. Multivariable analyses adjusting for known factors confirmed CPT1Ahigh as a high risk factor. Significant associations between CPT1Ahigh and adverse outcomes were further validated whether for all AML patients (OS: P = 0.008; EFS: P = 0.002, n = 334, no M3) or for National Comprehensive Cancer Network (NCCN) Intermediate-Risk subgroup (OS: P = 0.021, EFS: P = 0.024, n = 173). Multiple omics analysis revealed aberrant alterations of genomics and epigenetics were significantly associated with CPT1A expression, including up- and down-regulation of oncogenes and tumor suppressor, activation and inhibition of leukemic (AML, CML) and immune activation pathways, hypermethylation enrichments on CpG island and gene promoter regions. Combined with the previously reported anti-leukemia activity of CPT1A's inhibitor, our results proved CPT1A as a potential prognosticator and therapeutic target for AML.

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“…Acute myeloid leukemia tumors have also been shown to be dependent on arginine for proliferation. 57 …”

Section: Resultsmentioning

confidence: 99%

Identifying Cancer Specific Metabolic Signatures Using Constraint-Based Models

Schultz

Mehta

et al. 2016

Biocomputing 2017

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Cancer metabolism differs remarkably from the metabolism of healthy surrounding tissues, and it is extremely heterogeneous across cancer types. While these metabolic differences provide promising avenues for cancer treatments, much work remains to be done in understanding how metabolism is rewired in malignant tissues. To that end, constraint-based models provide a powerful computational tool for the study of metabolism at the genome scale. To generate meaningful predictions, however, these generalized human models must first be tailored for specific cell or tissue sub-types. Here we first present two improved algorithms for (1) the generation of these context-specific metabolic models based on omics data, and (2) Monte-Carlo sampling of the metabolic model flux space. By applying these methods to generate and analyze context-specific metabolic models of diverse solid cancer cell line data, and primary leukemia pediatric patient biopsies, we demonstrate how the methodology presented in this study can generate insights into the rewiring differences across solid tumors and blood cancers.

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Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Cited by 132 publications

References 62 publications

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

High Expression of CPT1A Predicts Adverse Outcomes: A Potential Therapeutic Target for Acute Myeloid Leukemia

Identifying Cancer Specific Metabolic Signatures Using Constraint-Based Models

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