scholarly journals Evi1 Upregulates Fbp1 and Supports Progression of Acute Myeloid Leukemia through Pentose Phosphate Pathway Activation

2021 ◽  
Author(s):  
Hideaki Mizuno ◽  
Junji Koya ◽  
Yosuke Masamoto ◽  
Yuki Kagoya ◽  
Mineo Kurokawa
Keyword(s):  
Acute Myeloid Leukemia ◽  
Pentose Phosphate Pathway ◽  
Myeloid Leukemia ◽  
Pentose Phosphate ◽  
Pathway Activation ◽  
Acute Myeloid

Novel Genomic Patterns of Metabolic Remodeling in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3837-3837
Author(s):  
Giorgia Simonetti ◽  
Antonella Padella ◽  
Ítalo Faria do Valle ◽  
Gabriele Fontanarosa ◽  
Elisa Zago ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cancer Cell ◽  
Pentose Phosphate Pathway ◽  
Myeloid Leukemia ◽  
Pentose Phosphate ◽  
Transcriptional Analysis ◽  
Chemotherapy Response ◽  
Genomic Alterations ◽  
Metabolic Remodeling ◽  
Acute Myeloid

Abstract Metabolic remodeling of cancer is controlled by metabolic enzymes having oncogenic or tumor suppressor functions, along with oncogenes and tumor suppressors, which cooperate with the tissue environment to define specific metabolic profiles (Yuneva et al. Cell met 2012). Dysregulated metabolic pathways contribute to the pathogenesis of Acute Myeloid Leukemia (AML), as demonstrated for IDH1/2 mutations, which force the production of the oncometabolite 2-Hydroxyglutarate (Ward et al. Cancer Cell 2010) and can be selectively targeted (Wang et al. Science 2013). However, the genetic determinants of leukemia metabolic plasticity are largely unexplored. To identify metabolism-related pathogenic mechanisms in AML, we screened 886 AML cases for targeted genomic alterations and performed Whole Exome Sequencing of 143 leukemia samples (100 bp paired-end, HiSeq2000, Illumina), focusing our analysis on 37 AML cases (34 at diagnosis and 3 at relapse). Mutations were called by MuTect and GATK. Moreover, transcriptional analysis was performed on bone marrow cells from 59 AML cases (≥80% blasts) and 7 healthy controls (HTA2.0, Affymetrix). By mapping the mutated genes into functional categories, we identified a previously undescribed class of mutations targeting metabolism-related genes, that we define metabolic acute leukemia genes (MALGs). MALG was the most represented category after signaling pathways (76/915 genomic alterations) and 29/37 patients carried at least one MALG mutation. MALG mutations mostly targeted biosynthesis and catabolism of lipids and of CoA (ACP2, PANK2), bioenergetic pathways, metabolism of amino acids and nucleotides (NUDT18, IMPDH2). Notably, IMPDH2 is a target of MYC, a known regulator of cancer cell metabolism, and balances the nucleotide pool required for DNA replication (Liu et al, Plos one 2008). IMPDH2 was not only mutated but also upregulated at mRNA level in AML compared with controls (p=0.0001), suggesting an oncogenic function of the gene in AML, which is under investigation. Moreover, MYC transcriptional network was affected by additional mutations targeting genes regulating MYC activity (HUWE1, ZBTB17, TRRAP) and degradation (HEPACAM). Mutations in amino acid metabolism affected the synthesis/degradation of serine (PHGDH), glycine (SHMT2), proline (PRODH), tryptophan(CYP1B1) and glutamate (OPLAH), with a glutamate-related metabolic signature being also enriched in AML. These results may be highly relevant to AML therapy, since they may identify patients suitable to glutaminase inhibitor treatment, which is under development by pharmaceutical companies. An additional subset of patients displayed mutations in glucose-dependent bioenergetic pathways: glycolysis (GPI), oxidative phosphorylation (ND1, ND4, ND5, CYTB) and pentose phosphate pathway (H6PD, PGLS). These mutations were mutually exclusive with KRAS/NRAS alterations, which were detected in 8/37 samples. Indeed, oncogenic KRAS stimulates glucose uptake and channeling of glucose intermediates into pentose phosphate pathway (Ying et al. Cell 2012). Mutations in the bioenergetic pathways occurred across different cytogenetic groups and were associated with a poor outcome in terms of overall survival (p=0.016 Fig.1) in our AML cohort. Along with mutations in KRAS- and MYC-oncogenic pathways, which are known to control metabolic processes, we identified a novel functional category of mutated genes involved in metabolism (MALG) in AML. Our results may suggest different types of metabolic remodeling across leukemia subgroups. Mutations targeting a common downstream metabolic pathway are mutually exclusive in our cohort, as shown by KRAS and genes involved in glucose-dependent bioenergetic processes. Glucose metabolism predicts clinical outcome and chemotherapy response in AML (Chen et al. Blood 2014). Our data further suggest that the mutational screening of glucose-related MALGs may define a new subgroup of patients, which could not be identified by cytogenetic analysis. These findings may have implication for AML treatment, since metabolic alterations and genomic determinants of metabolic remodeling are promising targets for tailored therapies, as recently shown for glutaminase and IDH1/2 inhibitors. Acknowledgments: EHA Research Fellowship award, FP7 NGS-PTL project, ELN, AIL, AIRC, progetto Regione-Università 2010-12 Disclosures Soverini: Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Cavo:JANSSEN, CELGENE, AMGEN: Consultancy. Martinelli:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; MSD: Consultancy; Ariad: Consultancy; BMS: Consultancy, Speakers Bureau; ROCHE: Consultancy; AMGEN: Consultancy.

Age-Specific Differences in Oncogenic Pathway Dysregulation in Patients With Acute Myeloid Leukemia

2009 ◽  
Vol 27 (33) ◽  
pp. 5580-5586 ◽  
Author(s):  
Arati V. Rao ◽  
Peter J.M. Valk ◽  
Klaus H. Metzeler ◽  
Chaitanya R. Acharya ◽  
Sascha A. Tuchman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Treatment Strategies ◽  
Gene Set Enrichment Analysis ◽  
Oncogenic Signaling ◽  
Younger Patients ◽  
Pathway Activation ◽  
Acute Myeloid

Purpose To define the biology driving the aggressive nature of acute myeloid leukemia (AML) in elderly patients. Patients and Methods Clinically annotated microarray data from 425 patients with newly diagnosed de novo AML from two publicly available data sets were analyzed after age-specific cohorts (young ≤ 45 years, n = 175; elderly ≥ 55 years; n = 144) were prospectively identified. Gene expression analysis was conducted utilizing gene set enrichment analysis, and by applying previously defined and tested signature profiles reflecting dysregulation of oncogenic signaling pathways and altered tumor environment. Results Elderly AML patients as expected had worse overall survival and event-free survival compared with younger patients. Analysis of oncogenic pathways revealed that older patients had higher probability of RAS, Src, and tumor necrosis factor (TNF) pathway activation (all P < .0001). Hierarchical clustering revealed that younger patients with AML in cluster 2 had clinically worse survival, with high RAS, Src, and TNF pathway activation compared with patients in cluster 1. However, among elderly patients with AML, those in cluster 1 also demonstrated high RAS, Src, and TNF pathway activation but this did not translate into differences in survival. Conclusion AML in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathway variations that contributes to poor survival. These insights should enable development and adjustments of clinically meaningful treatment strategies in the older patient population.

scholarly journals STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia

Cell Reports ◽  
2016 ◽  
Vol 15 (11) ◽  
pp. 2357-2366 ◽  
Author(s):  
Emily Curran ◽  
Xiufen Chen ◽  
Leticia Corrales ◽  
Douglas E. Kline ◽  
Thomas W. Dubensky ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pathway Activation ◽  
Sting Pathway ◽  
Acute Myeloid

scholarly journals Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and resensitizes acute myeloid leukemia to BCL-2 inhibition

Haematologica ◽  
2020 ◽  
Author(s):  
Bing Z. Carter ◽  
Po Yee Mak ◽  
Wenjing Tao ◽  
Marc Warmoes ◽  
Philip L. Lorenzi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Metabolism ◽  
Acquired Resistance ◽  
Leukemia Cell ◽  
Tca Cycle ◽  
Pentose Phosphate ◽  
Leukemia Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia and critical for the survival of acute myeloid leukemia cells and acute myeloid leukemia stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and pharmacological approaches, we discovered that MCL-1 regulates leukemia cell bioenergetics and carbohydrate metabolisms, including the TCA cycle, glycolysis and pentose phosphate pathway and modulates cell adhesion proteins and leukemia-stromal interactions. Inhibition of MCL-1 sensitizes to BCL-2 inhibition in acute myeloid leukemia cells and acute myeloid leukemia stem/progenitor cells, including those with intrinsic and acquired resistance to venetoclax through cooperative release of pro-apoptotic BIM, BAX, and BAK from binding to anti-apoptotic BCL-2 proteins and inhibition of cell metabolism and key stromal microenvironmental mechanisms. The combined inhibition of MCL-1 by MCL-1 inhibitor AZD5991 or CDK9 inhibitor AZD4573 and BCL-2 by venetoclax greatly extended survival of mice bearing patient-derived xenografts established from an acute myeloid leukemia patient who acquired resistance to venetoclax/decitabine. These results demonstrate that co-targeting MCL-1 and BCL-2 improves the efficacy of and overcomes preexisting and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered functions of MCL-1 in acute myeloid leukemia, which are independent from canonical regulation of apoptosis by MCL-1. Our data provide new mechanisms of synergy and rationale for co-targeting MCL-1 and BCL-2 clinically in patients with acute myeloid leukemia and potentially other cancers.

Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia

2019 ◽  
Vol 9 (8) ◽  
pp. 1050-1063 ◽  
Author(s):  
Christine M. McMahon ◽  
Timothy Ferng ◽  
Jonathan Canaani ◽  
Eunice S. Wang ◽  
Jennifer J.D. Morrissette ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clonal Selection ◽  
Ras Pathway ◽  
Pathway Activation ◽  
Clinical Resistance ◽  
Acute Myeloid

scholarly journals Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

Aging ◽  
2016 ◽  
Vol 8 (11) ◽  
pp. 2936-2947 ◽  
Author(s):  
Ivan Petrov ◽  
Maria Suntsova ◽  
Olga Mutorova ◽  
Maxim Sorokin ◽  
Andrew Garazha ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pediatric Acute Myeloid Leukemia ◽  
Molecular Pathway ◽  
Pathway Activation ◽  
Acute Lymphoblast Leukemia ◽  
Acute Myeloid
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