bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–11–06
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Tumor glycolysis, an essential sweet tooth of tumor cells.
  2. Resistance to targeted therapies in acute myeloid leukemia.
  3. Prognostic impact of unsupervised early assessment of bulk and leukemic stem cell measurable residual disease in acute myeloid leukemia.
  4. Cell-intrinsic factors governing quiescence vis-à-vis activation of adult hematopoietic stem cells.
  5. Could SIRPA expression predict response to anti-PD-1 immunotherapy?
  6. A functional analysis of 180 cancer cell lines reveals conserved intrinsic metabolic programs.
  7. Mechanisms of venetoclax resistance and solutions.
  8. Editorial: Lineage tracing, hematopoietic stem cell and immune cell dynamics.
  9. Targeting CD38 for acute leukemia.
  10. Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
  11. Mitochondria from the Outside in: The Relationship Between Inter-Organelle Crosstalk and Mitochondrial Internal Organization.
  1. Semin Cancer Biol. 2022 Oct 28. pii: S1044-579X(22)00204-8. [Epub ahead of print]86(Pt 3): 1216-1230
    Tumor glycolysis, an essential sweet tooth of tumor cells.
    Sumana Paul, Saikat Ghosh, Sushil Kumar.
      Cancer cells undergo metabolic alterations to meet the immense demand for energy, building blocks, and redox potential. Tumors show glucose-avid and lactate-secreting behavior even in the presence of oxygen, a process known as aerobic glycolysis. Glycolysis is the backbone of cancer cell metabolism, and cancer cells have evolved various mechanisms to enhance it. Glucose metabolism is intertwined with other metabolic pathways, making cancer metabolism diverse and heterogeneous, where glycolysis plays a central role. Oncogenic signaling accelerates the metabolic activities of glycolytic enzymes, mainly by enhancing their expression or by post-translational modifications. Aerobic glycolysis ferments glucose into lactate which supports tumor growth and metastasis by various mechanisms. Herein, we focused on tumor glycolysis, especially its interactions with the pentose phosphate pathway, glutamine metabolism, one-carbon metabolism, and mitochondrial oxidation. Further, we describe the role and regulation of key glycolytic enzymes in cancer. We summarize the role of lactate, an end product of glycolysis, in tumor growth, and the metabolic adaptations during metastasis. Lastly, we briefly discuss limitations and future directions to improve our understanding of glucose metabolism in cancer.
    Keywords:  Cancer metabolism; Lactate; Metastasis; Tumor glycolysis; metabolic adaptations
    DOI:  https://doi.org/10.1016/j.semcancer.2022.09.007
  2. Clin Exp Metastasis. 2022 Nov 01.
    Resistance to targeted therapies in acute myeloid leukemia.
    Rabea Mecklenbrauck, Michael Heuser.
      The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or secondary resistance mechanisms. In this review, we summarize the current knowledge on the main mechanisms of resistance to targeted therapies in AML. Resistance to FLT3 inhibitors is mainly mediated by on target mutations and dysregulation of downstream pathways. Switching the FLT3 inhibitor has a potential therapeutic benefit. During treatment with IDH inhibitors resistance can develop due to aberrant cell metabolism or secondary site IDH mutations. As a unique resistance mechanism the mutated IDH isotype may switch from IDH1 to IDH2 or vice versa. Resistance to gemtuzumab-ozogamicin is determined by the CD33 isotype and the degradation of the cytotoxin. The main mechanisms of resistance to venetoclax are the dysregulation of alternative pathways especially the upregulation of the BCL-2-analogues MCL-1 and BCL-XL or the induction of an aberrant cell metabolism. The introduction of therapies targeting immune processes will lead to new forms of therapy resistance. Knowing those mechanisms will help to develop strategies that can overcome resistance to treatment.
    Keywords:  FLT3 inhibitors; Gemtuzumab-ozogamicin; IDH inhibitors; Primary resistance; Venetoclax
    DOI:  https://doi.org/10.1007/s10585-022-10189-0
  3. Clin Cancer Res. 2022 Nov 01. pii: CCR-22-2237. [Epub ahead of print]
    Prognostic impact of unsupervised early assessment of bulk and leukemic stem cell measurable residual disease in acute myeloid leukemia.
    Alban Canali, Inès Vergnolle, Sarah Bertoli, Laetitia Largeaud, Marie-Laure Nicolau, Jean-Baptiste Rieu, Suzanne Tavitian, Francoise Huguet, Muriel Picard, Pierre Bories, Jean-Philippe Vial, Nicolas Lechevalier, Marie-Christine Béné, Isabelle Luquet, Véronique Mansat-De Mas, Eric Delabesse, Christian Recher, Francois Vergez.
       PURPOSE: Acute myeloid leukemias (AML) are clonal diseases that develop from leukemic stem cells (LSCs) that carry an independent prognostic impact on the initial response to induction chemotherapy, demonstrating the clinical relevance of LSC abundance in AML. In 2018, the European LeukemiaNet has published recommendations for the detection of measurable residual disease (Bulk MRD) and suggested the exploration of LSC MRD and the use of multiparametric displays.
    EXPERIMENTAL DESIGN: We evaluated the performance of unsupervised clustering for the post-induction assessment of bulk and LSC MRD in 155 AML patients who received intensive conventional chemotherapy treatment.
    RESULTS: The median overall survival (OS) for Bulk+ MRD patients was 16.7 months and was not reached for negative patients (Hazard Ratio, HR:3.82, p<0.0001). The median OS of LSC+ MRD patients was 25.0 months and not reached for negative patients (HR:2.84, p=0.001). Interestingly, one-year (y) and 3-y OS were 60% and 39% in Bulk+, 91% and 52% in Bulk-LSC+ and 92% and 88% in Bulk-LSC-.
    CONCLUSION: In this study, we confirm the prognostic impact of post-induction MFC Bulk MRD in AML patients. Focusing on LSCs, we identified a group of patients with negative Bulk MRD but positive LSC MRD (25.8% of our cohort) with an intermediate prognosis, demonstrating the interest of MRD analysis focusing on leukemic chemoresistant subpopulations.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2237
  4. Mol Cell Biochem. 2022 Oct 30.
    Cell-intrinsic factors governing quiescence vis-à-vis activation of adult hematopoietic stem cells.
    Pallavi Budgude, Anuradha Vaidya, Vaijayanti Kale.
      Hematopoiesis is a highly complex process, regulated by both intrinsic and extrinsic factors. Often, these two regulatory arms work in tandem to maintain the steady-state condition of hematopoiesis. However, at times, certain intrinsic attributes of hematopoietic stem cells (HSCs) override the external stimuli and dominate the outcome. These could be genetic events like mutations or environmentally induced epigenetic or transcriptomic changes. Since leukemic stem cells (LSCs) share molecular pathways that also regulate normal HSCs, identifying specific, dominantly acting intrinsic factors could help in the development of novel therapeutic approaches. Here we have reviewed such dominantly acting intrinsic factors governing quiescence vis-à-vis activation of the HSCs in the face of external forces acting on them. For brevity, we have restricted our review to the articles dealing with adult HSCs of human and mouse origin that have been published in the last 10 years. Hematopoietic stem cells (HSCs) are closely associated with various stromal cells in their microenvironment and, thus, constantly receive signaling cues from them. The illustration depicts some dominantly acting intrinsic or cell-autonomous factors operative in the HSCs. These fall into various categories, such as epigenetic regulators, transcription factors, cell cycle regulators, tumor suppressor genes, signaling pathways, and metabolic regulators, which counteract the outcome of extrinsic signaling exerted by the HSC niche.
    Keywords:  Activation; Acute myeloid leukemia; Hematopoietic stem cells; Intrinsic regulators; Quiescence
    DOI:  https://doi.org/10.1007/s11010-022-04594-y
  5. Cancer Cell. 2022 Oct 26. pii: S1535-6108(22)00494-9. [Epub ahead of print]
    Could SIRPA expression predict response to anti-PD-1 immunotherapy?
    Kristen Jogerst, Genevieve Boland.
      Immune checkpoint inhibitors (ICIs) offer significant promise for patients with melanoma; however, many patients succumb to de novo or acquired ICI resistance. In this issue of Cancer Cell, Zhou et al. propose a mechanism for signal-regulatory protein α1 (SIRPα) expression and describe how its loss may contribute to immunotherapy resistance.
    DOI:  https://doi.org/10.1016/j.ccell.2022.10.003
  6. Mol Syst Biol. 2022 11;18(11): e11033
    A functional analysis of 180 cancer cell lines reveals conserved intrinsic metabolic programs.
    Sarah Cherkaoui, Stephan Durot, Jenna Bradley, Susan Critchlow, Sebastien Dubuis, Mauro Miguel Masiero, Rebekka Wegmann, Berend Snijder, Alaa Othman, Claus Bendtsen, Nicola Zamboni.
      Cancer cells reprogram their metabolism to support growth and invasion. While previous work has highlighted how single altered reactions and pathways can drive tumorigenesis, it remains unclear how individual changes propagate at the network level and eventually determine global metabolic activity. To characterize the metabolic lifestyle of cancer cells across pathways and genotypes, we profiled the intracellular metabolome of 180 pan-cancer cell lines grown in identical conditions. For each cell line, we estimated activity for 49 pathways spanning the entirety of the metabolic network. Upon clustering, we discovered a convergence into only two major metabolic types. These were functionally confirmed by 13 C-flux analysis, lipidomics, and analysis of sensitivity to perturbations. They revealed that the major differences in cancers are associated with lipid, TCA cycle, and carbohydrate metabolism. Thorough integration of these types with multiomics highlighted little association with genetic alterations but a strong association with markers of epithelial-mesenchymal transition. Our analysis indicates that in absence of variations imposed by the microenvironment, cancer cells adopt distinct metabolic programs which serve as vulnerabilities for therapy.
    Keywords:  cancer metabolism; cell lines; metabolic flux; metabolomics; omics
    DOI:  https://doi.org/10.15252/msb.202211033
  7. Front Oncol. 2022 ;12 1005659
    Mechanisms of venetoclax resistance and solutions.
    Jiachen Liu, Yidong Chen, Lihua Yu, Lihua Yang.
      The BCL-2 inhibitor venetoclax is currently approved for treatment of hematologic diseases and is widely used either as monotherapy or in combination strategies. It has produced promising results in the treatment of refractory or relapsed (R/R) and aged malignant hematologic diseases. However, with clinical use, resistance to venetoclax has emerged. We review the mechanism of reduced dependence on BCL-2 mediated by the upregulation of antiapoptotic proteins other than BCL-2, such as MCL-1 and BCL-XL, which is the primary mechanism of venetoclax resistance, and find that this mechanism is achieved through different pathways in different hematologic diseases. Additionally, this paper also summarizes the current investigations of the mechanisms of venetoclax resistance in terms of altered cellular metabolism, changes in the mitochondrial structure, altered or modified BCL-2 binding domains, and some other aspects; this article also reviews relevant strategies to address these resistance mechanisms.
    Keywords:  BCL-2 protein; gene mutations; metabolism; mitochondria; oxphos; resistance; venetoclax
    DOI:  https://doi.org/10.3389/fonc.2022.1005659
  8. Front Immunol. 2022 ;13 1062415
    Editorial: Lineage tracing, hematopoietic stem cell and immune cell dynamics.
    Caleb A Lareau, Chiara Romagnani, Leif S Ludwig.
      
    Keywords:  cancer biology; clonal dynamics; hematopoietic stem cells; immunology; lineage tracing; single cell multi-omics
    DOI:  https://doi.org/10.3389/fimmu.2022.1062415
  9. Front Oncol. 2022 ;12 1007783
    Targeting CD38 for acute leukemia.
    Xushu Zhong, Hongbing Ma.
      Acute leukemia (AL) is a hematological malignancy, and the prognosis of most AL patients hasn't improved significantly, particularly for relapsed or refractory (R/R) AL. Therefore, new treatments for R/R adult acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are urgently necessary. Novel developments have been made in AL treatment, including target and immune therapies. CD38 is one of the targets due to its high expression in many hematological malignancies, including multiple myeloma, ALL and a subset of AML. Consequently, targeting CD38 therapies, including CD38 monoclonal antibodies (mAbs), bispecific antibodies, and CAR-T cell therapy, exhibit promising efficacy in treating multiple myeloma without significant toxicity and are being explored in other hematological malignancies and nonhematological diseases. Herein, this review focuses on targeting CD38 therapies in ALL and AML, which demonstrate sound antileukemic effects in acute leukemia and are expected to become effective treatment methods.
    Keywords:  CD38mAb; acute lymphoblastic leukemia; acute myeloid leukemia; anti-CD38 CAR T; bispecific antibodies
    DOI:  https://doi.org/10.3389/fonc.2022.1007783
  10. Mol Cell. 2022 Oct 31. pii: S1097-2765(22)00962-5. [Epub ahead of print]
    Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
    Patricia Altea-Manzano, Anke Vandekeere, Joy Edwards-Hicks, Mar Roldan, Emily Abraham, Xhordi Lleshi, Ania Naila Guerrieri, Domenica Berardi, Jimi Wills, Jair Marques Junior, Asimina Pantazi, Juan Carlos Acosta, Rosario M Sanchez-Martin, Sarah-Maria Fendt, Miguel Martin-Hernandez, Andrew J Finch.
      Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.
    Keywords:  anaplerosis; cancer; cancer metabolism; metabolism; mitochondrion; redox; redox transfer; respiration
    DOI:  https://doi.org/10.1016/j.molcel.2022.10.005
  11. Contact (Thousand Oaks). 2022 Jan-Dec;5:5
    Mitochondria from the Outside in: The Relationship Between Inter-Organelle Crosstalk and Mitochondrial Internal Organization.
    Jonathan R Friedman.
      A fundamental role of membrane-bound organelles is the compartmentalization and organization of cellular processes. Mitochondria perform an immense number of metabolic chemical reactions and to efficiently regulate these, the organelle organizes its inner membrane into distinct morphological domains, including its characteristic cristae membranes. In recent years, a structural feature of increasing apparent importance is the inter-connection between the mitochondrial exterior and other organelles at membrane contact sites (MCSs). Mitochondria form MCSs with almost every other organelle in the cell, including the endoplasmic reticulum, lipid droplets, and lysosomes, to coordinate global cellular metabolism with mitochondrial metabolism. However, these MCSs not only facilitate the transport of metabolites between organelles, but also directly impinge on the physical shape and functional organization inside mitochondria. In this review, we highlight recent advances in our understanding of how physical connections between other organelles and mitochondria both directly and indirectly influence the internal architecture of mitochondria.
    Keywords:  Ca2+; cristae; endoplasmic reticulum; inner mitochondrial membrane; interorganelle (inter-organelle); lipid droplet; lysosome; mitochondrion (mitochondria); phospholipid
    DOI:  https://doi.org/10.1177/25152564221133267
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