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Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α). We identified a key naphthamide scaffold that depleted both intended targets in acute myeloid leukemia MOLM-13 cells. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound DEG-35. A subsequent scaffold replacement campaign identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in the diffuse large B cell lymphoma cell line OCI-LY3 and the ovarian cancer cell line A2780 indicating that the dual degrader strategy may have efficacy against additional types of cancer.
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Caseína Quinasa Ialfa , Neoplasias Ováricas , Humanos , Femenino , Línea Celular Tumoral , Lenalidomida/farmacología , Ubiquitina-Proteína Ligasas/metabolismo , Caseína Quinasa Ialfa/metabolismo , Proteolisis , Factor de Transcripción Ikaros/metabolismoRESUMEN
BACKGRUOUND: Radiation exposure is a well-known risk factor for papillary thyroid cancer (PTC). South Korea has 24 nuclear reactors in operation; however, no molecular biological analysis has been performed on patients with PTC living near nuclear power plants. METHODS: We retrospectively included patients with PTC (n=512) divided into three groups according to their place of residence at the time of operation: inland areas (n=300), coastal areas far from nuclear power plants (n=134), and nuclear power plant areas (n=78). After propensity score matching (1:1:1) by age, sex, and surgical procedure, the frequency of representative driver mutations and gene expression profiles were compared (n=50 per group). Epithelial-mesenchymal transition (EMT), BRAF, thyroid differentiation, and radiation scores were calculated and compared. RESULTS: No significant difference was observed in clinicopathological characteristics, including radiation exposure history and the frequency of incidentally discovered thyroid cancer, among the three groups. BRAFV600E mutation was most frequently detected in the groups, with no difference among the three groups. Furthermore, gene expression profiles showed no statistically significant difference. EMT and BRAF scores were higher in our cohort than in cohorts from Chernobyl tissue bank and The Cancer Genome Atlas Thyroid Cancer; however, there was no difference according to the place of residence. Radiation scores were highest in the Chernobyl tissue bank but exhibited no difference according to the place of residence. CONCLUSION: Differences in clinicopathological characteristics, frequency of representative driver mutations, and gene expression profiles were not observed according to patients' region of residence in South Korea.
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Carcinoma Papilar , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/complicaciones , Transcriptoma , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/genética , Mutación , República de Corea/epidemiologíaRESUMEN
INTRODUCTION: Ultrasonography (US) features of papillary thyroid cancers (PTCs) are used to select nodules for biopsy due to their association with tumor behavior. However, the molecular biological mechanisms that lead to the characteristic US features of PTCs are largely unknown. OBJECTIVES: This study aimed to investigate the molecular biological mechanisms behind US features assessed by radiologists and three convolutional neural networks (CNN) through transcriptome analysis. METHODS: Transcriptome data from 273 PTC tissue samples were generated and differentially expressed genes (DEGs) were identified according to US feature. Pathway enrichment analyses were also conducted by gene set enrichment analysis (GSEA) and ClusterProfiler according to assessments made by radiologists and three CNNs - CNN1 (ResNet50), CNN2 (ResNet101) and CNN3 (VGG16). Signature gene scores for PTCs were calculated by single-sample GSEA (ssGSEA). RESULTS: Individual suspicious US features consistently suggested an upregulation of genes related to immune response and epithelial-mesenchymal transition (EMT). Likewise, PTCs assessed as positive by radiologists and three CNNs showed the coordinate enrichment of similar gene sets with abundant immune and stromal components. However, PTCs assessed as positive by radiologists had the highest number of DEGs, and those assessed as positive by CNN3 had more diverse DEGs and gene sets compared to CNN1 or CNN2. The percentage of PTCs assessed as positive or negative concordantly by radiologists and three CNNs was 85.6% (231/273) and 7.1% (3/273), respectively. CONCLUSION: US features assessed by radiologists and CNNs revealed molecular biologic features and tumor microenvironment in PTCs.
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Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1α (CK1α), termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic-specific transcription factor that contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α, which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and induces myeloid differentiation in AML cells through CK1α-p53- and IKZF2-dependent pathways. Target degradation by DEG-35 or a more soluble analog, DEG-77, delays leukemia progression in murine and human AML mouse models. Overall, we provide a strategy for multitargeted degradation of IKZF2 and CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.
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Caseína Quinasa Ialfa , Leucemia Mieloide Aguda , Animales , Humanos , Ratones , Caseína Quinasa Ialfa/genética , Caseína Quinasa Ialfa/metabolismo , Hematopoyesis , Factor de Transcripción Ikaros/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Factores de TranscripciónAsunto(s)
Carcinoma Papilar , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Metástasis Linfática , Carcinoma Papilar/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/secundarioRESUMEN
To identify potent antiviral compounds, we introduced a high-throughput screen platform that can rapidly classify hit compounds according to their target. In our platform, we performed a compound screen using a lentivirus-based pseudovirus presenting a spike protein of coronavirus, and we evaluated the hit compounds using an amplified luminescence proximity homogeneous assay (alpha) test with purified host receptor protein and the receptor binding domain of the viral spike. With our screen platform, we were able to identify both spike-specific compounds (class I) and broad-spectrum antiviral compounds (class II). Among the hit compounds, thiosemicarbazide was identified to be selective to the interaction between the viral spike and its host cell receptor, and we further optimized the binding potency of thiosemicarbazide through modification of the pyridine group. Among the class II compounds, we found raloxifene and amiodarone to be highly potent against human coronaviruses including Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2. In particular, using analogs of the benzothiophene moiety, which is also present in raloxifene, we have identified benzothiophene as a novel structural scaffold for broad-spectrum antivirals. This work highlights the strong utility of our screen platform using a pseudovirus assay and an alpha test for rapid identification of potential antiviral compounds and their mechanism of action, which can lead to the accelerated development of therapeutics against newly emerging viral infections.
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COVID-19 , Coronavirus del Síndrome Respiratorio de Oriente Medio , Humanos , Luminiscencia , Clorhidrato de Raloxifeno , SARS-CoV-2/metabolismo , Antivirales/farmacología , Antivirales/química , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Cancer progression is associated with metabolic reprogramming and causes significant intracellular stress; however, the mechanisms that link cellular stress and growth signalling are not fully understood. Here, we identified a mechanism that couples the mitochondrial stress response (MSR) with tumour progression. We demonstrated that the MSR is activated in a significant proportion of human thyroid cancers via the upregulation of heat shock protein D family members and the mitokine, growth differentiation factor 15. Our study also revealed that MSR triggered AKT/S6K signalling by activating mTORC2 via activating transcription factor 4/sestrin 2 activation whilst promoting leucine transporter and nutrient-induced mTORC1 activation. Importantly, we found that an increase in mtDNA played an essential role in MSR-induced mTOR activation and that crosstalk between MYC and MSR potentiated mTOR activation. Together, these findings suggest that the MSR could be a predictive marker for aggressive human thyroid cancer as well as a useful therapeutic target.
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Proteínas Proto-Oncogénicas c-akt , Neoplasias de la Tiroides , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patologíaRESUMEN
The thyroid gland plays an essential role in the regulation of body energy expenditure to maintain metabolic homeostasis. However, to date, there are no studies investigating the morphological and functional changes of the thyroid gland due to mitochondrial stress in metabolic organs such as the liver. We used data from the Genotype-Tissue Expression portal to investigate RNA expression patterns of the thyroid gland according to the expression of growth differentiation factor 15 (GDF15) such as the muscles and liver. To verify the effect of hepatic GDF15 on the thyroid gland, we compared the morphological findings of the thyroid gland from liver-specific GDF15 transgenic mice to that of wild type mice. High GDF15 expression in the muscles and liver was associated with the upregulation of genes related to hypoxia, inflammation (TGF-α via NFκB), apoptosis, and p53 pathway in thyroid glands. In addition, high hepatic GDF15 was related to epithelial mesenchymal transition and mTORC1 signaling. Electron microscopy for liver-specific GDF15 transgenic mice revealed short mitochondrial cristae length and small mitochondrial area, indicating reduced mitochondrial function. However, serum thyroid stimulating hormone (TSH) level was not significantly different. In our human cohort, those with a high serum GDF15 level showed high fasting glucose, alanine transaminase, and alkaline phosphatase but no difference in TSH, similar to the data from our mice model. Additionally, high serum GDF15 increased the risk of lymph node metastasis to lateral neck. The hepatic GDF15 affected thyroid morphogenesis via a TSH-independent mechanism, affecting aggressive features of thyroid cancers.
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Factor 15 de Diferenciación de Crecimiento , Glándula Tiroides , Animales , Factor 15 de Diferenciación de Crecimiento/genética , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Hígado/metabolismo , Ratones , Ratones Transgénicos , Glándula Tiroides/metabolismo , Tirotropina/metabolismoRESUMEN
Regulatory T (Treg) cells represent a specialized lineage of suppressive CD4+ T cells whose functionality is critically dependent on their ability to migrate to and dwell in the proximity of cells they control. Here we show that continuous expression of the chemokine receptor CXCR4 in Treg cells is required for their ability to accumulate in the bone marrow (BM). Induced CXCR4 ablation in Treg cells led to their rapid depletion and consequent increase in mature B cells, foremost the B-1 subset, observed exclusively in the BM without detectable changes in plasma cells or hematopoietic stem cells or any signs of systemic or local immune activation elsewhere. Dysregulation of BM B-1 B cells was associated with a highly specific increase in IgM autoantibodies and total serum IgM levels. Thus, Treg cells control autoreactive B-1 B cells in a CXCR4-dependent manner. These findings have significant implications for understanding the regulation of B cell autoreactivity and malignancies.
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Subgrupos de Linfocitos B , Linfocitos T Reguladores , Subgrupos de Linfocitos B/metabolismo , Médula Ósea/metabolismo , Células de la Médula Ósea/metabolismo , Inmunoglobulina M/metabolismo , Receptores CXCR4/metabolismoRESUMEN
Notch signaling is a druggable target in high-grade serous ovarian cancers; however, its complexity is not clearly understood. Recent revelations of the biological roles of lncRNAs have led to an increased interest in the oncogenic action of lncRNAs in various cancers. In this study, we performed in silico analyses using The Cancer Genome Atlas data to discover novel Notch-related lncRNAs and validated our transcriptome data via NOTCH1/3 silencing in serous ovarian cancer cells. The expression of novel Notch-related lncRNAs was down-regulated by a Notch inhibitor and was upregulated in high-grade serous ovarian cancers, compared to benign or borderline ovarian tumors. Functionally, Notch-related lncRNAs were tightly linked to Notch-related changes in diverse gene expressions. Notably, genes related to DNA repair and spermatogenesis showed specific correlations with Notch-related lncRNAs. Master transcription factors, including EGR1, CTCF, GABPα, and E2F4 might orchestrate the upregulation of Notch-related lncRNAs, along with the associated genes. The discovery of Notch-related lncRNAs significantly contributes to our understanding of the complex crosstalk of Notch signaling with other oncogenic pathways at the transcriptional level.
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Increasing numbers of cancer stem cell markers have been recently identified. It is not known, however, whether a member of the nuclear receptor superfamily, thyroid hormone receptor ß (TRß), can function to regulate cancer stem cell (CSC) activity. Using anaplastic thyroid cancer cells (ATC) as a model, we highlight the role of TRß in CSC activity. ATC is one of the most aggressive solid cancers in humans and is resistant to currently available therapeutics. Recent studies provide evidence that CSC activity underlies aggressiveness and therapeutic resistance of ATC. Here we show that TRß inhibits CSC activity by suppressing tumor-sphere formation of human ATC cells and their tumor-initiating capacity. TRß suppresses the expression of CSC regulators, including ALDH, KLF2, SOX2, b-catenin, and ABCG2, in ATC cell-induced xenograft tumors. Single-cell transcriptomic analysis shows that TRß reduces CSC population in ATC-induced xenograft tumors. Analysis of The Cancer Genome Atlas (TCGA) database demonstrates that the inhibition of CSC capacity by TRß contributes to favorable clinical outcomes in human cancer. Our studies show that TRß is a newly identified transcription regulator that acts to suppress CSC activity and that TRß could be considered as a molecular target for therapeutic intervention of ATC.
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Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Línea Celular Tumoral , Humanos , Células Madre Neoplásicas/patología , Carcinoma Anaplásico de Tiroides/genética , Receptores beta de Hormona Tiroidea/genética , Receptores beta de Hormona Tiroidea/metabolismo , Neoplasias de la Tiroides/patologíaRESUMEN
Anaplastic thyroid cancer (ATC) is a highly aggressive type of thyroid cancer (TC). Currently, no effective target treatments are available that can improve overall survival, with ATC representing a major clinical challenge because of its remarkable lethality. Tumor-associated macrophages (TAMs) are the most evident cells in ATCs, and their high density is correlated with a poor prognosis. However, the mechanisms of how TAMs promote ATC progression remain poorly characterized. Here, we demonstrated that the treatment of human monocytes (THP-1 cells) with ATC cell-derived conditioned media (CM) promoted macrophage polarization, showing high levels of M2 markers. Furthermore, we found that STAT3 was activated, and this was correlated with an increased expression and secretion of the inflammatory cytokine interleukin-6. Remarkably, the M2-like macrophages obtained revealed tumor-promoting activity. A cytokine array analysis demonstrated that M2-like macrophage-derived CM contained high levels of TIM3, which is an important immune regulatory molecule. Consistently, TIM3 expression was up-regulated in THP-1 cells cultured with ATC cell-derived CM. Moreover, TIM3 blockade significantly reversed the polarization of THP-1 cells induced by ATC cell-secreted soluble factors. We validated the clinical significance of the TIM3 in human TC by analyzing public datasets and found that the expression of TIM3 and its ligand galectin 9 was significantly higher in human TC tissue samples than in normal thyroid tissues. Taken together, our findings identified a new mechanism by which TIM3 induces tumor-promoting M2-like macrophage polarization in TC. Furthermore, TIM3 interference might be a potential tool for treatment of patients with ATC.
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Caprifoliaceae s.l. plastid genomes (plastomes) show that one inversion and two inverted repeat boundary shifts occurred in the common ancestor of this family, after which the plastomes are generally conserved. This study reports plastome sequences of five additional species, Fedia cornucopiae, Valeriana fauriei, and Valerianella locusta from the subfamily Valerianoideae, as well as Dipsacus japonicus and Scabiosa comosa from the subfamily Dipsacoideae. Combined with the published plastomes, these plastomes provide new insights into the structural evolution of plastomes within the family. Moreover, the three plastomes from the subfamily Valerianoideae exhibited accelerated nucleotide substitution rates, particularly at synonymous sites, across the family. The patterns of accD sequence divergence in the family are dynamic with structural changes, including interruption of the conserved domain and increases in nonsynonymous substitution rates. In particular, the Valeriana accD gene harbors a large insertion of amino acid repeat (AAR) motifs, and intraspecific polymorphism with a variable number of AARs in the Valeriana accD gene was detected. We found a correlation between intron losses and increased ratios of nonsynonymous to synonymous substitution rates in the clpP gene with intensified positive selection. In addition, two Dipsacoideae plastomes revealed the loss of the plastid-encoded rps15, and a potential functional gene transfer to the nucleus was confirmed.
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Caprifoliaceae/genética , Proteínas de Cloroplastos/genética , Genoma de Plastidios , Inversión de Secuencia , Secuencias de Aminoácidos , Caprifoliaceae/clasificación , Especificidad de la EspecieRESUMEN
The phenylpropanoid pathway is a major secondary metabolite pathway that helps plants overcome biotic and abiotic stress and produces various byproducts that promote human health. Its byproduct caffeoylquinic acid is a soluble phenolic compound present in many angiosperms. Hydroxycinnamate-CoA shikimate/quinate transferase is a significant enzyme that plays a role in accumulating CQA biosynthesis. This study analyzed transcriptome-wide identification of the phenylpropanoid to caffeoylquinic acid biosynthesis candidate genes in A. spathulifolius flowers and leaves. Transcriptomic analyses of the flowers and leaves showed a differential expression of the PPP and CQA biosynthesis regulated unigenes. An analysis of PPP-captive unigenes revealed a major duplication in the following genes: PAL, 120 unigenes in leaves and 76 in flowers; C3'H, 169 unigenes in leaves and 140 in flowers; 4CL, 41 unigenes in leaves and 27 in flowers; and C4H, 12 unigenes in leaves and 4 in flowers. The phylogenetic analysis revealed 82 BAHDs superfamily members in leaves and 72 in flowers, among which five unigenes encode for HQT and three for HCT. The three HQT are common to both leaves and flowers, whereas the two HQT were specialized for leaves. The pattern of HQT synthesis was upregulated in flowers, whereas HCT was expressed strongly in the leaves of A. spathulifolius. Overall, 4CL, C4H, and HQT are expressed strongly in flowers and CAA and HCT show more expression in leaves. As a result, the quantification of HQT and HCT indicates that CQA biosynthesis is more abundant in the flowers and synthesis of caffeic acid in the leaves of A. spathulifolius.
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Aciltransferasas/genética , Asteraceae/enzimología , Asteraceae/genética , Vías Biosintéticas , Ácido Quínico/análogos & derivados , Transcriptoma/genética , Vías Biosintéticas/genética , Flores/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Ontología de Genes , Anotación de Secuencia Molecular , Filogenia , Hojas de la Planta/genética , Propanoles/metabolismo , Ácido Quínico/metabolismoRESUMEN
We investigated the regulatory mechanism of FAL1 and unravelled the molecular biological features of FAL1 upregulation in papillary thyroid cancer (PTC). Correlation analyses of FAL1 and neighbouring genes adjacent to chromosome 1q21.3 were performed. Focal amplification was performed using data from copy number alterations in The Cancer Genome Atlas (TCGA) database. To identify putative transcriptional factors, PROMO and the Encyclopaedia of DNA Elements (ENCODE) were used. To validate c-JUN and JUND as master transcription factors for FAL1 and ECM1, gene set enrichment analysis was performed according to FAL1 and ECM1 expression. Statistical analyses of the molecular biological features of FAL1- and ECM1-upregulated PTCs were conducted. FAL1 expression significantly correlated with that of neighbouring genes. Focal amplification of chromosome 1q21.3 was observed in ovarian cancer but not in thyroid carcinoma. However, PROMO suggested 53 transcription factors as putative common transcriptional factors for FAL1 and ECM1 simultaneously. Among them, we selected c-JUN and JUND as the best candidates based on ENCODE results. The expression of target genes of JUND simultaneously increased in FAL1- and ECM1-upregulated PTCs, especially in young patients. The molecular biological features represented RAS-driven PTC and simultaneously enriched immune-related gene sets. FAL1 and ECM1 expression frequently increased simultaneously and could be operated by JUND. The simultaneous upregulation might be a potential diagnostic and therapeutic target for RAS-driven PTC.
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In the current study, we followed 839 household contacts (HHCs) of tuberculosis (TB) patients for 2 years and identified the factors that enhanced the development of TB. Fourteen of the 17 HHCs who progressed to TB were in the 15- to 30-year-old age group. At baseline (the "0" time point, when all the individuals were healthy), the concentration of the thyroid hormone thyroxine (T4) was lower, and there were increased numbers of Tregs in PBMCs of TB progressors. At baseline, PBMCs from TB progressors stimulated with early secretory antigenic target 6 (ESAT-6) and 10 kDa culture filtrate antigen (CFP-10) produced less IL-1α. Thyroid hormones inhibited Mycobacterium tuberculosis (Mtb) growth in macrophages in an IL-1α-dependent manner. Mtb-infected Thra1PV/+ (mutant thyroid hormone receptor) mice had increased mortality and reduced IL-1α production. Our findings suggest that young HHCs who exhibit decreased production of thyroid hormones are at high risk of developing active TB disease.
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Leucocitos Mononucleares/inmunología , Mycobacterium tuberculosis , Linfocitos T Reguladores/inmunología , Tiroxina , Adolescente , Adulto , Animales , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Progresión de la Enfermedad , Transmisión de Enfermedad Infecciosa/estadística & datos numéricos , Composición Familiar , Femenino , Humanos , Interleucina-1alfa/metabolismo , Masculino , Ratones , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/aislamiento & purificación , Factores Protectores , Tiroxina/biosíntesis , Tiroxina/sangre , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiologíaRESUMEN
A bra use can reduce physiological and physical functions because of clothing pressure, which can be a problem for new senior women starting to lose physical function. The present study presents a bra top design development method for promoting new senior women's physical activity by identifying problems related to bras' effects on women's health and minimizing clothing pressure. The analysis utilized the 3D scan data of 42 adult women (age range: 50s) from the 5th Size Korea Project. Bra top design elements were extracted based on new senior consumers' needs. We developed an average wireframe reflecting the new senior's physical characteristics, and a standard body form was developed through surface modeling. To produce a consumer-oriented bra with a body shaping effect and reduced clothing pressure that would not affect physical activities, a three-dimensional pattern was developed applying an optimal reduction rate of 80%. To verify the bra's adequacy for the body form of new senior women, two market-available bras were selected and fit-compared to the developed product. The developed bra received higher expert appearance evaluation and 3D virtual clothing evaluation scores. This study is significant because by using virtual fitting technology, it provides foundational data to quantify the quality of fashion products.
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Mama , Vestuario , Adulto , Ejercicio Físico , Femenino , Estado de Salud , Humanos , Persona de Mediana Edad , República de CoreaRESUMEN
A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions. This metabolic program is mediated by the ratio of redox cofactors, NAD+/NADH, and the increased SSP flux is beneficial for generating alpha-ketoglutarate from glutamine, which allows leukemic cells to proliferate even in the absence of glucose. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, dramatically reduces leukemia engraftment in mice in the presence of high fructose, confirming the essential role of the SSP in the metabolic plasticity of leukemic cells.