bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–08–21
thirteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells.
  2. CD123 Antagonistic Peptides Assembled with Nanomicelles Act as Monotherapeutics to Combat Refractory Acute Myeloid Leukemia.
  3. Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids.
  4. Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia.
  5. Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia.
  6. Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.
  7. Dietary methionine starvation impairs acute myeloid leukemia progression.
  8. Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies.
  9. Interleukin-33: Metabolic checkpoints, metabolic processes, and epigenetic regulation in immune cells.
  10. NF-κB: blending metabolism, immunity, and inflammation.
  11. Shining a light on hematopoietic stem cells.
  12. Endothelial-leukemia interactions remodel drug responses uncovering T-ALL vulnerabilities.
  13. Immune Checkpoint Inhibitors: Recent clinical advances and future prospects.
  1. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)00995-0. [Epub ahead of print]40(7): 111182
    Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells.
    Emily Gruber, Joan So, Alexander C Lewis, Rheana Franich, Rachel Cole, Luciano G Martelotto, Amy J Rogers, Eva Vidacs, Peter Fraser, Kym Stanley, Lisa Jones, Anna Trigos, Niko Thio, Jason Li, Brandon Nicolay, Scott Daigle, Adriana E Tron, Marc L Hyer, Jake Shortt, Ricky W Johnstone, Lev M Kats.
      Approximately 20% of acute myeloid leukemia (AML) patients carry mutations in IDH1 or IDH2 that result in over-production of the oncometabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission; however, almost all patients eventually acquire drug resistance and relapse. Using a multi-allelic mouse model of IDH1-mutant AML, we demonstrate that the clinical IDH1 inhibitor AG-120 (ivosidenib) exerts cell-type-dependent effects on leukemic cells, promoting delayed disease regression. Although single-agent AG-120 treatment does not fully eradicate the disease, it increases cycling of rare leukemia stem cells and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitizes IDH1-mutant AML to azacitidine, with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide a mechanistic rationale for the observed combinatorial effect of AG-120 and azacitidine in patients.
    Keywords:  2-HG; CP: cancer; IDH1; ivosidenib; leukemia stem cells; non-genetic heterogeneity; pyrimidine salvage
    DOI:  https://doi.org/10.1016/j.celrep.2022.111182
  2. ACS Appl Mater Interfaces. 2022 Aug 17.
    CD123 Antagonistic Peptides Assembled with Nanomicelles Act as Monotherapeutics to Combat Refractory Acute Myeloid Leukemia.
    Shilin Xu, Meichen Zhang, Xiaocui Fang, Xuechun Hu, Haiyan Xing, Yanlian Yang, Jie Meng, Tao Wen, Jian Liu, Jianxiang Wang, Chen Wang, Haiyan Xu.
      Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Due to the development of drug resistance to traditional chemotherapies and high relapse rate, AML still has a low survival rate and there is in an urgent need for better treatment strategies. CD123 is widely expressed by AML cells, also associated with the poor prognosis of AML. In this study, we fabricated nanomicelles loaded with a lab-designed CD123 antagonistic peptide, which were referred to as mPO-6. The antagonistic and therapeutic effects were investigated with CD123+ AML cell lines and a refractory AML mouse (AE and CKITD816V) model. Results show that mPO-6 can specifically bind to the CD123+ AML cells and inhibit the cell viability effectively. Intravenous administration of mPO-6 significantly reduces the percentage of AML cells' infiltration and prolongs the median survival of AML mice. Further, the efficiency of mPO-6 is demonstrated to interfere with the axis of CD123/IL-3 via regulating the activation of STAT5, PI3K/AKT, and NF-κB signaling pathways related to cell proliferation or apoptosis at the level of mRNA and protein in vivo and in vitro. In conclusion, the novel CD123 antagonistic peptide micelle formulation mPO-6 can significantly enhance apoptosis and prolong the survival of AML mice by effectively interfering with the axis of CD123/IL-3 and therefore is a promising therapeutic candidate for the treatment of refractory AML.
    Keywords:  CD123; acute myeloid leukemia; antagonistic; nanomicelles; refractory
    DOI:  https://doi.org/10.1021/acsami.2c11538
  3. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01015-4. [Epub ahead of print]40(7): 111198
    Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids.
    Mahmud O Abdullah, Run X Zeng, Chelsea L Margerum, David Papadopoli, Cian Monnin, Kaylee B Punter, Charles Chu, Mohammad Al-Rofaidi, Naser F Al-Tannak, Domenica Berardi, Zahra Rattray, Nicholas J W Rattray, Sheela A Abraham, Eeva-Liisa Eskelinen, David G Watson, Daina Avizonis, Ivan Topisirovic, Edmond Y W Chan.
      The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid starvation display clear mitochondrial fusion as a means to evade mitophagy. Surprisingly, further supplementation of glutamine (Q), leucine (L), and arginine (R) did not reverse, but produced stronger mitochondrial hyperfusion. Interestingly, the hyperfusion response to Q + L + R was dependent upon mitochondrial fusion proteins Mfn1 and Opa1 but was independent of MTORC1. Metabolite profiling indicates that Q + L + R addback replenishes amino acid and nucleotide pools. Inhibition of fumarate hydratase, glutaminolysis, or inosine monophosphate dehydrogenase all block Q + L + R-dependent mitochondrial hyperfusion, which suggests critical roles for the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses further support the idea that supplemented Q promotes purine biosynthesis by serving as a donor of amine groups. We thus describe a metabolic mechanism for direct sensing of cellular amino acids to control mitochondrial fusion and cell fate.
    Keywords:  CP: Cell biology; CP: Metabolism; Drp1; Mfn1; Mfn2; Opa1; amino acid sensing; arginine; dynamics; fusion; glutamine; hyperfusion; leucine; mitochondria; stable isotope tracer
    DOI:  https://doi.org/10.1016/j.celrep.2022.111198
  4. Mol Cancer. 2022 Aug 19. 21(1): 166
    Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia.
    Yanan Zhai, Prashant Singh, Anna Dolnik, Peter Brazda, Nader Atlasy, Nunzio Del Gaudio, Konstanze Döhner, Hartmut Döhner, Saverio Minucci, Joost Martens, Lucia Altucci, Wout Megchelenbrink, Lars Bullinger, Hendrik G Stunnenberg.
       BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts in the hematopoietic system. The heterogeneity and evolution of cancer blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. In this study, we investigated the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs at genetic and transcriptional levels, and unveiled the underlying pathways and genes contributing to recurrence.
    METHODS: Whole-exome sequencing was used to detect somatic mutations and large copy number variations (CNVs). Single cell RNA-seq was performed to investigate the clonal heterogeneity between Dx-Re pairs and amongst patients.
    RESULTS: scRNA-seq analysis revealed extensive expression differences between patients and Dx-Re pairs, even for those with the same -presumed- initiating events. Transcriptional differences between and within patients are associated with clonal composition and evolution, with the most striking differences in patients that gained large-scale copy number variations at relapse. These differences appear to have significant molecular implications, exemplified by a DNMT3A/FLT3-ITD patient where the leukemia switched from an AP-1 regulated clone at Dx to a mTOR signaling driven clone at Re. The two distinct AML1-ETO pairs share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells evolved from the Dx cells.
    CONCLUSIONS: In summary, the single cell RNA data underpinned the tumor heterogeneity not only amongst patient blasts with similar initiating mutations but also between each Dx-Re pair. Our results suggest alternatively and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence.
    Keywords:  Acute myeloid Leukemia; Genome analysis; Leukemic stem cells; Recurrence; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1186/s12943-022-01635-4
  5. Blood Cancer J. 2022 Aug 16. 12(8): 117
    Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia.
    François Vergez, Laetitia Largeaud, Sarah Bertoli, Marie-Laure Nicolau, Jean-Baptiste Rieu, Inès Vergnolle, Estelle Saland, Audrey Sarry, Suzanne Tavitian, Françoise Huguet, Muriel Picard, Jean-Philippe Vial, Nicolas Lechevalier, Audrey Bidet, Pierre-Yves Dumas, Arnaud Pigneux, Isabelle Luquet, Véronique Mansat-De Mas, Eric Delabesse, Martin Carroll, Gwenn Danet-Desnoyers, Jean-Emmanuel Sarry, Christian Récher.
      Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte-monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.
    DOI:  https://doi.org/10.1038/s41408-022-00712-7
  6. Mol Cell. 2022 Aug 12. pii: S1097-2765(22)00703-1. [Epub ahead of print]
    Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.
    Yahui Wang, Ethan Stancliffe, Ronald Fowle-Grider, Rencheng Wang, Cheng Wang, Michaela Schwaiger-Haber, Leah P Shriver, Gary J Patti.
      Proliferating cells exhibit a metabolic phenotype known as "aerobic glycolysis," which is characterized by an elevated rate of glucose fermentation to lactate irrespective of oxygen availability. Although several theories have been proposed, a rationalization for why proliferating cells seemingly waste glucose carbon by excreting it as lactate remains elusive. Using the NCI-60 cell lines, we determined that lactate excretion is strongly correlated with the activity of mitochondrial NADH shuttles, but not proliferation. Quantifying the fluxes of the malate-aspartate shuttle (MAS), the glycerol 3-phosphate shuttle (G3PS), and lactate dehydrogenase under various conditions demonstrated that proliferating cells primarily transform glucose to lactate when glycolysis outpaces the mitochondrial NADH shuttles. Increasing mitochondrial NADH shuttle fluxes decreased glucose fermentation but did not reduce the proliferation rate. Our results reveal that glucose fermentation, a hallmark of cancer, is a secondary consequence of MAS and G3PS saturation rather than a unique metabolic driver of cellular proliferation.
    Keywords:  NADH shuttles; aerobic glycolysis; cancer metabolism; glycerol 3-phosphate shuttle; isotope-tracer analysis; malate-aspartate shuttle; metabolic flux; metabolomics; the Warburg effect
    DOI:  https://doi.org/10.1016/j.molcel.2022.07.007
  7. Blood. 2022 Aug 19. pii: blood.2022017575. [Epub ahead of print]
    Dietary methionine starvation impairs acute myeloid leukemia progression.
    Alan Cunningham, Ayşegül Erdem, Islam Alshamleh, Marjan Geugien, Maurien Pruis, Diego A Pereira-Martins, Fiona van den Heuvel, Albertus Wierenga, Hilde Anna Ten Berge, Robin Dennebos, Vincent van den Boom, Shanna M Hogeling, Isabel Weinhäuser, Ruth Knops, Pim de Blaauw, M Rebecca Heiner-Fokkema, Carolien Woolthuis, Ulrich Günther, Eduardo M Rego, Joost Martens, Joop H Jansen, Harald Schwalbe, Gerwin Huls, Jan Jacob Schuringa.
      Targeting altered tumor cell metabolism might provide an attractive opportunity for patients with acute myeloid leukemia (AML). An amino acid dropout screen on primary leukemic stem cells and progenitor populations revealed a number of amino acid dependencies, of which methionine was one of the strongest. By using various metabolite rescue experiments, NMR-based metabolite quantifications and 13C-tracing, polysomal profiling, and ChIP-seq, we identified that methionine is used predominantly for protein translation and to provide methyl groups to histones via S-adenosylmethionine for epigenetic marking. H3K36me3 was consistently the most heavily impacted mark following loss of methionine. Methionine depletion also reduced total RNA levels, enhanced apoptosis and induced a cell cycle block. ROS levels were not increased following methionine depletion and replacement of methionine with glutathione or N-acetylcysteine could not rescue phenotypes, excluding a role for methionine in controlling redox balance control in AML. Although considered to be an essential amino acid, methionine can be recycled from homocysteine. We uncovered that this is primarily performed by the enzyme methionine synthase and only when methionine availability becomes limiting. In vivo, dietary methionine starvation was not only tolerated by mice, but also significantly delayed both cell line and patient-derived AML progression. Finally, we show that inhibition of the H3K36-specific methyltransferase SETD2 phenocopies much of the cytotoxic effects of methionine depletion, providing a more targeted therapeutic approach. In conclusion, we show that methionine depletion is a vulnerability in AML that can be exploited therapeutically, and we provide mechanistic insight into how cells metabolize and recycle methionine.
    DOI:  https://doi.org/10.1182/blood.2022017575
  8. Front Immunol. 2022 ;13 943354
    Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies.
    Kamira Maharaj, Angimar Uriepero, Eva Sahakian, Javier Pinilla-Ibarz.
      Regulatory T cells (Tregs) are responsible for maintaining immune homeostasis by controlling immune responses. They can be characterized by concomitant expression of FoxP3, CD25 and inhibitory receptors such as PD-1 and CTLA-4. Tregs are key players in preventing autoimmunity and are dysregulated in cancer, where they facilitate tumor immune escape. B-cell lymphoid malignancies are a group of diseases with heterogenous molecular characteristics and clinical course. Treg levels are increased in patients with B-cell lymphoid malignancies and correlate with clinical outcomes. In this review, we discuss studies investigating Treg immunobiology in B-cell lymphoid malignancies, focusing on clinical correlations, mechanisms of accumulation, phenotype, and function. Overarching trends suggest that Tregs can be induced directly by tumor cells and recruited to the tumor microenvironment where they suppress antitumor immunity to facilitate disease progression. Further, we highlight studies showing that Tregs can be modulated by novel therapeutic agents such as immune checkpoint blockade and targeted therapies. Treg disruption by novel therapeutics may beneficially restore immune competence but has been associated with occurrence of adverse events. Strategies to achieve balance between these two outcomes will be paramount in the future to improve therapeutic efficacy and safety.
    Keywords:  B cell; BCL-2; BTK; PI3K; Treg; chronic lymphocytic leukemia; immune checkpoint blockade; non-Hodgkin’s lymphoma
    DOI:  https://doi.org/10.3389/fimmu.2022.943354
  9. Front Immunol. 2022 ;13 900826
    Interleukin-33: Metabolic checkpoints, metabolic processes, and epigenetic regulation in immune cells.
    Jian Lin, Jiyun Liu, Rui Ma, Jie Hao, Yan Liang, Junjie Zhao, Ailing Zhang, Haiyang Meng, Jingli Lu.
      Interleukin-33 (IL-33) is a pleiotropic cytokine linked to various immune cells in the innate and adaptive immune systems. Recent studies of the effects of IL-33 on immune cells are beginning to reveal its regulatory mechanisms at the levels of cellular metabolism and epigenetic modifications. In response to IL-33 stimulation, these programs are intertwined with transcriptional programs, ultimately determining the fate of immune cells. Understanding these specific molecular events will help to explain the complex role of IL-33 in immune cells, thereby guiding the development of new strategies for immune intervention. Here, we highlight recent findings that reveal how IL-33, acting as an intracellular nuclear factor or an extracellular cytokine, alters metabolic checkpoints and cellular metabolism, which coordinately contribute to cell growth and function. We also discuss recent studies supporting the role of IL-33 in epigenetic alterations and speculate about the mechanisms underlying this relationship.
    Keywords:  IL-33; epigenetics; immune cells; metabolic checkpoints; metabolic pathways
    DOI:  https://doi.org/10.3389/fimmu.2022.900826
  10. Trends Immunol. 2022 Aug 11. pii: S1471-4906(22)00141-7. [Epub ahead of print]
    NF-κB: blending metabolism, immunity, and inflammation.
    Daria Capece, Daniela Verzella, Irene Flati, Paola Arboretto, Jessica Cornice, Guido Franzoso.
      The procurement and management of nutrients and ability to fight infections are fundamental requirements for survival. These defense responses are bioenergetically costly, requiring the immune system to balance protection against pathogens with the need to maintain metabolic homeostasis. NF-κB transcription factors are central regulators of immunity and inflammation. Over the last two decades, these factors have emerged as a pivotal node coordinating the immune and metabolic systems in physiology and the etiopathogenesis of major threats to human health, including cancer, autoimmunity, chronic inflammation, and others. In this review, we discuss recent advances in understanding how NF-κB-dependent metabolic programs control inflammation, metabolism, and immunity and how improved knowledge of them may lead to better diagnostics and therapeutics for widespread human diseases.
    DOI:  https://doi.org/10.1016/j.it.2022.07.004
  11. Elife. 2022 Aug 19. pii: e81963. [Epub ahead of print]11
    Shining a light on hematopoietic stem cells.
    Anne Schmidt.
      A combination of light and electron microscopy has revealed further details about the location and interactions of hematopoietic stem and progenitor cells.
    Keywords:  correlative light; developmental biology; dopamine beta-hydroxylase; electron microscopy; hematopoietic stem cell; microenvironment; regenerative medicine; serial section blockface scanning electron microscopy; stem cell niche; stem cells; zebrafish
    DOI:  https://doi.org/10.7554/eLife.81963
  12. Blood. 2022 Aug 18. pii: blood.2022015414. [Epub ahead of print]
    Endothelial-leukemia interactions remodel drug responses uncovering T-ALL vulnerabilities.
    Luca Vincenzo Cappelli, Danilo Fiore, Jude M Phillip, Liron Yoffe, Filomena Di Giacomo, William Chiu, Yang Hu, Clarisse Kayembe, Michael Ginsberg, Lorena Consolino, José Gabriel Barcia Durán, Nahuel Zamponi, Ari M Melnick, Francesco Boccalatte, Wayne Tam, Olivier Elemento, Sabina Chiaretti, Anna Rita Guarini, Robin Foà, Leandro Cerchietti, Shahin Rafii, Giorgio Ga Inghirami.
      T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient-derived tumor-xenografts (PDX) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active compounds with anti-leukemia activity. Since endothelial cells (ECs) can alter drug responses in T-ALL, we developed an endothelial cells (ECs) / T-ALL co-culture system. We found that ECs provide pro-tumorigenic signals and mitigate drug responses to individual T-ALL PDX. ECs broadly rescued several compounds in most of the models, while other drugs were rescued only in individual PDXs suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, co-cultured T-ALL and ECs underwent bi-directional transcriptomic changes at the single-cell level, highlighting distinct "education signatures". These changes were linked to a bi-directional regulation of multiple pathways in T-ALL and ECs. Remarkably, in-vitro EC-educated T-ALL cells mirrored ex-vivo splenic T-ALL at the single-cell resolution. Lastly, five effective drugs from the two drug screenings were tested in vivo and shown to effectively delay tumor growth/dissemination and prolonging the overall survival (OS). We anticipate that this T-ALL-EC platform can contribute to elucidating leukemia-microenvironment interactions and identify effective compounds and therapeutic vulnerabilities.
    DOI:  https://doi.org/10.1182/blood.2022015414
  13. Curr Med Chem. 2022 Aug 19.
    Immune Checkpoint Inhibitors: Recent clinical advances and future prospects.
    Abid H Banday, Mohnad Abdalla.
      Immune checkpoints are vital molecules and pathways of the immune system with defined roles of controlling immune responses from being destructive to the healthy cells in the body. They include inhibitory receptors and ligands which keep in check the recognition of most of the cancers by the immune system. This happens when proteins on the surface of T cells called immune checkpoint proteins identify partner proteins on the cancer cells and bind to them sending brake signals to the T cells to evade immune attack. However, drugs called immune checkpoint inhibitors block checkpoint proteins from binding to their partner proteins thereby inhibiting the brake signals from being sent to T cells. This eventually allows the T cells to destroy cancer cells and arbitrate robust tumor regression. Many such inhibitors have already been approved and many are in various developmental stages. The well-illustrated inhibitory checkpoints include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Though many molecules blocking these checkpoints have shown promise in the treatment of many malignancies, there is yet limited success of such treatment options in terms of the immune response in majority of the patients. In this backdrop, exploration of new pathways and next-generation inhibitors becomes imperative for development of more responsive and effective immune checkpoint therapy. Owing to the complex biology and unexplored ambiguities in the mechanistic aspects of immune checkpoint pathways, analysis of the activity profile of new drugs is the subject of strenuous investigation. We herein report the recent progress in the development of new inhibitory pathways, potential therapeutics and delineate the developments based on their merit. Further, the ensuing challenges towards the development of efficacious checkpoint therapies and the impending opportunities are also discussed.
    Keywords:  CTLA-4; Cytotoxic T lymphocytes; Immune checkpoint pathway; Immunotherapy; PD-1; PD-L1.; tumor microenvironment
    DOI:  https://doi.org/10.2174/0929867329666220819115849
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