Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells

Jones, Courtney L.; Stevens, Brett M.; Pollyea, Daniel A.; Culp‐Hill, Rachel; Reisz, Julie A.; Nemkov, Travis; Gehrke, Sarah; Gamboni, Fabia; Krug, Anna; Winters, Amanda; Pei, Shanshan; Gustafson, Annika; Ye, Haobin; Inguva, Anagha; Amaya, M.F.; Minhajuddin, Mohammad; Becker, Michael W.; DeGregori, James; Smith, Clayton A.; D’Alessandro, Angelo; Jordan, Craig T.

doi:10.1016/j.stem.2020.07.021

Cited by 159 publications

(159 citation statements)

References 45 publications

(81 reference statements)

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“…Therefore, the role of CKS1 likely reaches further than cell cycle regulation, as has been previously reported(10,43). Here we provide evidence for CKS1 regulating RAC1/NADPH/ROS signalling (Figure 3H), a fundamental pathway involved in amplifying extrinsic and intrinsic signals in normal hematopoiesis and AML(4,44). The balance of intracellular ROS in normal and malignant hematopoietic cells has been of great interest in recent years(33,38), and changes in mitochondrial functions due to RAS mutations and nicotinamide-NAD metabolism underline the critical role for this pathway in primary patient resistance to Venetoclax(4,5).…”

Section: Discussionmentioning

confidence: 56%

“…Here we provide evidence for CKS1 regulating RAC1/NADPH/ROS signalling (Figure 3H), a fundamental pathway involved in amplifying extrinsic and intrinsic signals in normal hematopoiesis and AML(4,44). The balance of intracellular ROS in normal and malignant hematopoietic cells has been of great interest in recent years(33,38), and changes in mitochondrial functions due to RAS mutations and nicotinamide-NAD metabolism underline the critical role for this pathway in primary patient resistance to Venetoclax(4,5). The induction of ROS in AML cell lines upon CKS1 inhibition, regardless of CKS1B expression, demonstrates that the balance of CKS1-dependent protein degradation is key to maintaining stress responses in AML.…”

Section: Discussionmentioning

confidence: 56%

“…With the average two-year survival rate as low as 5-15% in poor risk, older patients (>65yr), there is an unmet critical need for new therapeutic approaches(1). Recent developments, targeting the anti-apoptotic protein BCL2, has demonstrated that therapies affecting protein networks holds great promise for the poorest prognosis AMLs(2,3), yet resistance still emerges for a subset of patients through mitochondrial adaptions in residual leukemic cells(4,5).…”

Section: Introductionmentioning

confidence: 99%

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CKS1-dependent proteostatic regulation has dual roles combating acute myeloid leukemia whilst protecting normal hematopoiesis

Grey

Río-Machín²,

Casado-Izquierdo³

et al. 2020

Preprint

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Acute myeloid leukemia (AML) is an aggressive hematological disorder comprising a hierarchy of quiescent leukemic stem cells (LSCs) and proliferating blasts with limited self-renewal ability. AML has a dismal prognosis, with extremely low two-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols unable to deplete LSCs, which reconstitute the disease in vivo, and the significant toxicity towards healthy hematopoietic cells. Whilst much work has been done to identify genetic and epigenetic vulnerabilities in AML LSCs, little is known about protein dynamics and the role of protein degradation in drug resistance and relapse. Here, using a highly specific inhibitor of the SCFSKP2-CKS1 complex, we report a dual role for CKS1-dependent protein degradation in reducing AML blasts in vivo, and importantly depleting LSCs. Whilst many AML LSC targeted therapies show significant toxicity to healthy hematopoiesis, inhibition of CKS1-dependent protein degradation has the opposite effect, protecting normal hematopoietic cells from chemotherapeutic toxicity. Together these findings demonstrate CKS1-dependent proteostasis is key for normal and malignant hematopoiesis.SignificanceCKS1-dependent protein degradation is a specific vulnerability in AML LSCs. Specific inhibition of SCFSKP2-CKS1 is lethal to CKS1Bhigh AML blasts and all AML LSCs. Normal hematopoiesis is protected from chemotherapeutic toxicity by inhibition of CKS1-dependent protein degradation, substantiating a dual role for CKS1-dependent protein degradation in clinical treatment of AML.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

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CKS1-dependent proteostatic regulation has dual roles combating acute myeloid leukemia whilst protecting normal hematopoiesis

Grey

Río-Machín²,

Casado-Izquierdo³

et al. 2020

Preprint

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“…Importantly, all these features define the BRAFi-resistant phenotype indicating that NAMPT over-expression per se recapitulates a resistance signature. A connection between NAMPT activity and invasive/stemness properties was recently reported in leukemia [ 33 ], glioma [ 34 ], colon [ 35 ] and breast [ 36 ] cancers. Our data supports the hypothesis that the phenotype plasticity of MM (oncogenic/invasive state ZEB1 high /TWIST1 high ) observed in BRAF mutated patients [ 23 ], responsible for disease progression and drug resistance [ 6 , 37 ], is recapitulated, at least in part, by NAMPT over-expression.…”

Section: Discussionmentioning

confidence: 97%

NAMPT Over-Expression Recapitulates the BRAF Inhibitor Resistant Phenotype Plasticity in Melanoma

Audrito

Messana

Moiso

et al. 2020

Cancers

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Serine–threonine protein kinase B-RAF (BRAF)-mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a driving factor in BRAFi resistance development. Using stable and inducible NAMPT over-expression systems, we showed that forced NAMPT expression in MM BRAF-mutated cell lines led to increased energy production, MAPK activation, colony-formation capacity, and enhance tumorigenicity in vivo. Moreover, NAMPT over-expressing cells switched toward an invasive/mesenchymal phenotype, up-regulating expression of ZEB1 and TWIST, two transcription factors driving the epithelial to mesenchymal transition (EMT) process. Consistently, within the NAMPT-overexpressing cell line variants, we observed an increased percentage of a rare, drug-effluxing stem cell-like side population (SP) of cells, paralleled by up-regulation of ABCC1/MRP1 expression and CD133-positive cells. The direct correlation between NAMPT expression and gene set enrichments involving metastasis, invasiveness and mesenchymal/stemness properties were verified also in melanoma patients by analyzing The Cancer Genome Atlas (TCGA) datasets. On the other hand, CRISPR/Cas9 full knock-out NAMPT BRAFi-resistant MM cells are not viable, while inducible partial silencing drastically reduces tumor growth and aggressiveness. Overall, this work revealed that NAMPT over-expression is both necessary and sufficient to recapitulate the BRAFi-resistant phenotype plasticity.

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“…Building up on their previous works, the group of Craig Jordan investigated the low response rate induced by venetoclax-based regimens in relapsed/refractory AML patients. 6 By comparing the metabolic profile of LSCs isolated from untreated patients or relapsed/refractory patients, the researchers demonstrated that relapsed/refractory LSCs have a unique metabolism which relies on nicotinamide. The authors demonstrated that LSCs metabolize nicotinamide into NAD + , which is an essential cofactor in enzymatic reactions occurring during the metabolism of aminoacids and the oxidation of fatty acids.…”

mentioning

confidence: 99%

Starving Drug Resistance

Tesio

2020

HemaSphere

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Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells

Cited by 159 publications

References 45 publications

CKS1-dependent proteostatic regulation has dual roles combating acute myeloid leukemia whilst protecting normal hematopoiesis

CKS1-dependent proteostatic regulation has dual roles combating acute myeloid leukemia whilst protecting normal hematopoiesis

NAMPT Over-Expression Recapitulates the BRAF Inhibitor Resistant Phenotype Plasticity in Melanoma

Starving Drug Resistance

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