bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021‒07‒11
fourteen papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

  1. Cancer Discov. 2021 May;2(3): 266-287
      We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML. SIGNIFICANCE: Reducing SIRT5 activity is detrimental to the survival of AML cells regardless of genotype, yet well tolerated by healthy hematopoietic cells. In mouse models, disrupting SIRT5 inhibits AML progression. SIRT5 controls several metabolic pathways that are required for leukemia cell survival. These results identify SIRT5 as a therapeutic target in AML.See related commentary by Li and Melnick, p. 198.
  2. Cancer Discov. 2021 Mar;2(2): 146-161
      TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant-derived 2-hydroxyglutarate is synthetically lethal to TET dioxygenase-deficient cells. In addition, a TET-selective small-molecule inhibitor decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses the clonal evolution of TET2-mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in TET2-mutant neoplasia. SIGNIFICANCE: Loss-of-function somatic TET2 mutations are among the most frequent lesions in myeloid neoplasms and associated disorders. Here we report a strategy for selective targeting of residual TET dioxygenase activity in TET-deficient clones that results in restriction of clonal evolution in vitro and in vivo.
  3. Front Cell Dev Biol. 2021 ;9 692940
      Cancer stem cells (CSCs) are subpopulations of undifferentiated cancer cells within the tumor bulk that are responsible for tumor initiation, recurrence and therapeutic resistance. The enhanced ability of CSCs to give rise to new tumors suggests potential roles of these cells in the evasion of immune surveillance. A growing body of evidence has described the interplay between CSCs and immune cells within the tumor microenvironment (TME). Recent data have shown the pivotal role of some major immune cells in driving the expansion of CSCs, which concurrently elicit evasion of the detection and destruction of various immune cells through a number of distinct mechanisms. Here, we will discuss the role of immune cells in driving the stemness of cancer cells and provide evidence of how CSCs evade immune surveillance by exerting their effects on tumor-associated macrophages (TAMs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), T-regulatory (Treg) cells, natural killer (NK) cells, and tumor-infiltrating lymphocytes (TILs). The knowledge gained from the interaction between CSCs and various immune cells will provide insight into the mechanisms by which tumors evade immune surveillance. In conclusion, CSC-targeted immunotherapy emerges as a novel immunotherapy strategy against cancer by disrupting the interaction between immune cells and CSCs in the TME.
    Keywords:  cancer; cancer stem cells; immune cells; immune evasion; tumor microenvironment
  4. Cancer Discov. 2021 May;2(3): 198-200
      In this issue of Blood Cancer Discovery, Yan and colleagues discovered that mitochondrial deacylase, SIRT5, is required in AML cells to support mitochondrial oxidative phosphorylation, maintain redox homeostasis, and drive glutaminolysis. The new SIRT5 inhibitor, NRD167, can efficiently target SIRT5 in AMLs at micromolar range and may constitute a novel therapeutic approach to improve clinical outcomes of patients with AML.See related article by Yan et al., p. 266.
  5. Cancer Discov. 2021 Jan;2(1): 3-5
      In this issue of Blood Cancer Discovery, Xie and colleagues describe a novel function of sphingosine-1-phosphate receptor 3 (S1PR3) to regulate myeloid differentiation and activate inflammatory programs in both human hematopoietic stem cells and leukemic stem cells. They propose S1PR3 as a major downstream signaling pathway of a TNFα-NF-κB axis in this study and unlock potential therapeutic opportunities to improve outcomes of patients with acute myeloid leukemia by modulating sphingolipid signaling via S1PR3.See related article by Xie et al., p. 32.
  6. Cell Mol Immunol. 2021 Jul 08.
      In 2011, Hanahan and Weinberg added "Deregulating Cellular Energetics" and "Avoiding Immune Destruction" to the six previous hallmarks of cancer. Since this seminal paper, there has been a growing consensus that these new hallmarks are not mutually exclusive but rather interdependent. The following review summarizes how founding genetic events for tumorigenesis ultimately increase tumor cell glycolysis, which not only supports the metabolic demands of malignancy but also provides an immunoprotective niche, promoting malignant cell proliferation, maintenance and progression. The mechanisms by which altered metabolism contributes to immune impairment are multifactorial: (1) the metabolic demands of proliferating tumor cells and activated immune cells are similar, thus creating a situation where immune cells may be in competition for key nutrients; (2) the metabolic byproducts of aerobic glycolysis directly inhibit antitumor immunity while promoting a regulatory immune phenotype; and (3) the gene programs associated with the upregulation of glycolysis also result in the generation of immunosuppressive cytokines and metabolites. From this perspective, we shed light on important considerations for the development of new classes of agents targeting cancer metabolism. These types of therapies can impair tumor growth but also pose a significant risk of stifling antitumor immunity.
    Keywords:  cancer; glycolysis; immunology; metabolism
  7. Dis Model Mech. 2021 Jul 01. 14(7): 1-17
      Cancer cells constantly reprogram their metabolism as the disease progresses. However, our understanding of the metabolic complexity of cancer remains incomplete. Extensive research in the fruit fly Drosophila has established numerous tumor models ranging from hyperplasia to neoplasia. These fly tumor models exhibit a broad range of metabolic profiles and varying nutrient sensitivity. Genetic studies show that fly tumors can use various alternative strategies, such as feedback circuits and nutrient-sensing machinery, to acquire and consolidate distinct metabolic profiles. These studies not only provide fresh insights into the causes and functional relevance of metabolic reprogramming but also identify metabolic vulnerabilities as potential targets for cancer therapy. Here, we review the conceptual advances in cancer metabolism derived from comparing and contrasting the metabolic profiles of fly tumor models, with a particular focus on the Warburg effect, mitochondrial metabolism, and the links between diet and cancer.
    Keywords:   Drosophila cancer models; Aerobic glycolysis; Metabolic reprogramming; Mitochondria
  8. Oncogene. 2021 Jul 08.
      Despite the fact that AML is the most common acute leukemia in adults, patient outcomes are poor necessitating the development of novel therapies. We identified that inhibition of Thioredoxin Reductase (TrxR) is a promising strategy for AML and report a highly potent and specific inhibitor of TrxR, S-250. Both pharmacologic and genetic inhibition of TrxR impairs the growth of human AML in mouse models. We found that TrxR inhibition leads to a rapid and marked impairment of metabolism in leukemic cells subsequently leading to cell death. TrxR was found to be a major and direct regulator of metabolism in AML cells through impacts on both glycolysis and the TCA cycle. Studies revealed that TrxR directly regulates GAPDH leading to a disruption of glycolysis and an increase in flux through the pentose phosphate pathway (PPP). The combined inhibition of TrxR and the PPP led to enhanced leukemia growth inhibition. Overall, TrxR abrogation, particularly with S-250, was identified as a promising strategy to disrupt AML metabolism.
  9. Mol Cancer Ther. 2021 Jun 17. pii: molcanther.MCT-20-0962-A.2020. [Epub ahead of print]
      ONC212 is a fluorinated-imipridone with preclinical efficacy against pancreatic and other malignancies. Although mitochondrial protease ClpP was identified as an ONC212-binding target, the mechanism leading to cancer cell death is incompletely understood. We investigated mitochondrial dysfunction and metabolic rewiring triggered by ONC212 in pancreatic cancer, a deadly malignancy with an urgent need for novel therapeutics. We found ClpP is expressed in pancreatic cancer cells and is required for ONC212 cytotoxicity. ClpX, the regulatory binding-partner of ClpP, is suppressed upon ONC212 treatment. Immunoblotting and extracellular flux analysis showed ONC212 impairs oxidative phosphorylation (OXPHOS) with decrease in mitochondrial-derived ATP production. Although collapse of mitochondrial function is observed across ONC212-treated cell lines, only OXPHOS-dependent cells undergo apoptosis. Cells relying on glycolysis undergo growth-arrest and upregulate glucose catabolism to prevent ERK1/2 inhibition and apoptosis. Glucose restriction or combination with glycolytic inhibitor 2-deoxy-D-glucose synergize with ONC212 and promote apoptosis in vitro and in vivo. Thus, ONC212 is a novel mitocan targeting oxidative-metabolism in pancreatic cancer, leading to different cellular outcomes based on divergent metabolic programs.
  10. Cancer Discov. 2021 Jan;2(1): 92-109
      Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell acute lymphoblastic leukemia (T-ALL). Here, we identify a highly conserved distal enhancer (PE) that interacts with the PTEN promoter in multiple hematopoietic populations, including T cells, and acts as a hub of relevant transcription factors in T-ALL. Consistently, loss of PE leads to reduced PTEN levels in T-ALL cells. Moreover, PE-null mice show reduced Pten levels in thymocytes and accelerated development of NOTCH1-induced T-ALL. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by Pten loss. Finally, we uncovered recurrent deletions encompassing PE in T-ALL, which are associated with decreased PTEN levels. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer. SIGNIFICANCE: Here, we identify a PTEN enhancer that is recurrently deleted in patients with T-ALL. Loss of this enhancer leads to reduced PTEN levels in T cells together with accelerated generation and progression of NOTCH1-induced leukemia in vivo. These results uncover long-range regulation of tumor suppressor genes as a relevant mechanism in cancer.This article is highlighted in the In This Issue feature, p. 1.
  11. Biochim Biophys Acta Rev Cancer. 2021 Jul 02. pii: S0304-419X(21)00082-2. [Epub ahead of print] 188585
      The tumor microenvironment plays a pivotal role in tumor initiation and progression by creating a dynamic interaction with cancer cells. The tumor microenvironment consists of various cellular components, including endothelial cells, fibroblasts, pericytes, adipocytes, immune cells, cancer stem cells and vasculature, which provide a sustained environment for cancer cell proliferation. Currently, targeting tumor microenvironment is increasingly being explored as a novel approach to improve cancer therapeutics, as it influences the growth and expansion of malignant cells in various ways. Despite continuous advancements in targeted therapies for cancer treatment, drug resistance, toxicity and immune escape mechanisms are the basis of treatment failure and cancer escape. Targeting tumor microenvironment efficiently with approved drugs and combination therapy is the solution to this enduring challenge that involves combining more than one treatment modality such as chemotherapy, surgery, radiotherapy, immunotherapy and nanotherapy that can effectively and synergistically target the critical pathways associated with disease pathogenesis. This review shed light on the composition of the tumor microenvironment, interaction of different components within tumor microenvironment with tumor cells and associated hallmarks, the current status of combinatorial therapies being developed, and various growing advancements. Furthermore, computational tools can also be used to monitor the significance and outcome of therapies being developed. We addressed the perceived barriers and regulatory hurdles in developing a combinatorial regimen and evaluated the present status of these therapies in the clinic. The accumulating depth of knowledge about the tumor microenvironment in cancer may facilitate further development of effective treatment modalities. This review presents the tumor microenvironment as a sweeping landscape for developing novel cancer therapies.
    Keywords:  Chemoresistance; Combination therapy; Hallmarks; Targeted therapies; Tumor microenvironment
  12. Nat Commun. 2021 Jul 06. 12(1): 4164
      Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.
  13. Cancer Cell Int. 2021 Jul 03. 21(1): 339
      Fatty acid oxidation (FAO) is the emerging hallmark of cancer metabolism because certain tumor cells preferentially utilize fatty acids for energy. Lymph node metastasis, the most common way of tumor metastasis, is much indispensable for grasping tumor progression, formulating therapy measure and evaluating tumor prognosis. There is a plethora of studies showing different ways how tumor cells metastasize to the lymph nodes, but the role of FAO in lymph node metastasis remains largely unknown. Here, we summarize recent findings and update the current understanding that FAO may enable lymph node metastasis formation. Afterward, it will open innovative possibilities to present a distinct therapy of targeting FAO, the metabolic rewiring of cancer to terminal cancer patients.
    Keywords:  Fatty acid oxidation; Immune suppression; Lymph node metastasis; Lymph node pre-metastatic niche; Metabolic reprogramming; Prognosis; YAP
  14. Expert Opin Emerg Drugs. 2021 Jul 06. 1-13
      Introduction: Patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) have historically poor outcomes with conventional chemotherapy regimens. Current treatment strategies focus on intensive induction therapy followed by allogeneic stem cell transplant or a less intensive approach with hypomethylating agents with or without venetoclax. CPX-351 is a liposomal formulation of cytarabine and daunorubicin that has been shown to significantly improve response rates and survival compared with 7 + 3 (continuous infusion cytarabine plus anthracyclines). Despite the approval of CPX-351 for AML-MRC, overall prognosis remains poor with an unmet need to develop novel therapeutic strategies for this patient population.Areas covered: This article reviews the data for existing therapeutic options for patients with AML-MRC and the emerging therapies undergoing clinical trial development for this patient population.Expert opinion: The development of CPX-351 as a more effective induction therapeutic backbone for patients with AML-MRC presents an opportunity to investigate novel combination regimens in order to further improve outcomes. Promising emerging therapeutic modalities include immunotherapeutic strategies, small-molecule inhibitors and targeted agents. Unfortunately, there have been few clinical trials focusing on patients with AML-MRC with reliance instead on subgroup analyses. Clinical trials focused specifically on this patient population are urgently needed.
    Keywords:  AML with myelodysplasia-related changes; Acute myeloid leukemia; aml; aml-mrc; induction chemotherapy; novel therapies; secondary aml; treatment