bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022‒09‒04
thirteen papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells.
  2. The Warburg effect: Saturation of mitochondrial NADH shuttles triggers aerobic lactate fermentation.
  3. Myeloid cell leukemia-1: a formidable barrier to anticancer therapeutics and the quest of targeting it.
  4. Chasing leukemia differentiation through induction therapy, relapse and transplantation.
  5. Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function.
  6. The lipid rafts in cancer stem cell: a target to eradicate cancer.
  7. Cellular hierarchies predict drug response in acute myeloid leukemia.
  8. A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure.
  9. Impact of mesenchymal stromal cell-derived vesicular cargo on B-cell acute lymphoblastic leukemia progression.
  10. Targeting endothelial cell metabolism in cancerous microenvironment: a new approach for anti-angiogenic therapy.
  11. A promising antitumor method: Targeting CSC with immune cells modified with CAR.
  12. Mitochondria in cancer: clean windmills or stressed tinkerers?
  13. Anoikis in cancer: The role of lipid signaling.
  1. Elife. 2022 Sep 02. pii: e75908. [Epub ahead of print]11
    Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells.
    Nuria Vilaplana-Lopera, Vincent Cuminetti, Ruba Almaghrabi, Grigorios Papatzikas, Ashok Kumar Rout, Mark Jeeves, Elena González, Yara Alyahyawi, Alan Cunnigham, Ayşegüll Erdem, Frank Schnütgen, Manoj Raghavan, Sandeep Potluri, Jean-Baptiste Cazier, Jan Jacob Schuringa, Michelle A C Reed, Lorena Arranz, Ulrich Günther, Paloma Garcia.
      Acute myeloid leukaemia (AML) cells interact and modulate components of their surrounding microenvironment into their own benefit. Stromal cells have been shown to support AML survival and progression through various mechanisms. Nonetheless, whether AML cells could establish beneficial metabolic interactions with stromal cells is underexplored. By using a combination of human AML cell lines and AML patient samples together with mouse stromal cells and a MLL-AF9 mouse model, here we identify a novel metabolic crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption to feed the tricarboxylic acid cycle (TCA) and lipid biosynthesis. By performing transcriptome analysis and tracer-based metabolic NMR analysis, we observe that stromal cells present a higher rate of glycolysis when co-cultured with AML cells. We also find that acetate in stromal cells is derived from pyruvate via chemical conversion under the influence of reactive oxygen species (ROS) following ROS transfer from AML to stromal cells via gap junctions. Overall, we present a unique metabolic communication between AML and stromal cells and propose two different molecular targets, ACSS2 and gap junctions, that could potentially be exploited for adjuvant therapy.
    Keywords:  biochemistry; cancer biology; chemical biology; human
    DOI:  https://doi.org/10.7554/eLife.75908
  2. Mol Cell. 2022 Sep 01. pii: S1097-2765(22)00757-2. [Epub ahead of print]82(17): 3119-3121
    The Warburg effect: Saturation of mitochondrial NADH shuttles triggers aerobic lactate fermentation.
    Hyllana C D Medeiros, Sophia Y Lunt.
      In this issue of Molecular Cell, Wang et al. investigate the Warburg effect in proliferating cells and demonstrate that lactate fermentation is a secondary mechanism activated after mitochondrial shuttles exceed their capacity to oxidize cytosolic NADH.
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.004
  3. Explor Target Antitumor Ther. 2022 ;3(3): 278-296
    Myeloid cell leukemia-1: a formidable barrier to anticancer therapeutics and the quest of targeting it.
    Prasad Sulkshane, Tanuja Teni.
      The antiapoptotic B cell lymphoma-2 (Bcl-2) family members are apical regulators of the intrinsic pathway of apoptosis that orchestrate mitochondrial outer membrane permeabilization (MOMP) through interactions with their proapoptotic counterparts. Overexpression of antiapoptotic Bcl-2 family proteins has been linked to therapy resistance and poor prognosis in diverse cancers. Among the antiapoptotic Bcl-2 family members, predominant overexpression of the prosurvival myeloid cell leukemia-1 (Mcl-1) has been reported in a myriad of hematological malignancies and solid tumors, contributing to therapy resistance and poor outcomes, thus making it a potential druggable target. The unique structure of Mcl-1 and its complex regulatory mechanism makes it an adaptive prosurvival switch that ensures tumor cell survival despite therapeutic intervention. This review focusses on diverse mechanisms adopted by tumor cells to maintain sustained elevated levels of Mcl-1 and how high Mcl-1 levels contribute to resistance in conventional as well as targeted therapies. Moreover, recent developments in the Mcl-1-targeted therapeutics and the underlying challenges and considerations in designing novel Mcl-1 inhibitors are also discussed.
    Keywords:  B cell lymphoma-2; Bcl-2 homology 3 mimetic; Myeloid cell leukemia-1; mitochondrial outer membrane permeabilization; myeloid cell leukemia-1 inhibitor; therapy resistance
    DOI:  https://doi.org/10.37349/etat.2022.00083
  4. Blood Rev. 2022 Aug 12. pii: S0268-960X(22)00074-1. [Epub ahead of print] 101000
    Chasing leukemia differentiation through induction therapy, relapse and transplantation.
    Jennifer N Saultz, Jeffrey W Tyner.
      Despite rapid advances in our understanding of acute myeloid leukemia (AML), the disease remains challenging to treat with 5-year survival for adult patients 20 years or older estimated to be 26% (Cancer 2021). The use of new targeted therapies including BCL2, IDH1/IDH2, and FLT3 inhibitors has revolutionized treatment approaches but also changed the disease trajectory with unique modes of resistance. Recent studies have shown that stem cell maturation state drives expression level and/or dependence on various pathways, critical to determining drug response. Instead of anticipating these changes, we remain behind the curve chasing the next expanded clone. This review will focus on current approaches to treatment in AML, including defining the significance of blast differentiation state on chemotherapeutic response, signaling pathway dependence, metabolism, immune response, and phenotypic changes. We conclude that multimodal treatment approaches are necessary to target both the immature and mature clones, thereby, sustaining drug response.
    Keywords:  AML; Chemotherapy; Differentiation; LSC; Maturation; Review
    DOI:  https://doi.org/10.1016/j.blre.2022.101000
  5. Blood Adv. 2022 Aug 31. pii: bloodadvances.2022008242. [Epub ahead of print]
    Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function.
    Yoshikane Kikushige, Toshihiro Miyamoto, Yu Kochi, Yuichiro Semba, Maki Ohishi, Hidetoshi Irifune, Kiwamu Hatakeyama, Yuya Kunisaki, Takeshi Sugio, Teppei Sakoda, Kohta Miyawaki, Koji Kato, Tomoyoshi Soga, Koichi Akashi.
      Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia-specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), and primary human acute myelogenous leukemia (AML) and lymphoblastic leukemia (ALL) cells. Here we show that human leukemia addicts to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG) and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids (BCKAs), whose metabolic processes provide leukemia cells with critical substrates for the TCA cycle and the non-essential amino acids synthesis, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates polycomb repressive complex 2 (PRC2) function, an epigenetic regulator for stem cell signatures, through inhibiting transcription of PRC components, such as zeste homolog 2 (EZH2) and embryonic ectoderm development (EED). Accordingly, BCAA catabolism plays an important role in maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008242
  6. Stem Cell Res Ther. 2022 Aug 30. 13(1): 432
    The lipid rafts in cancer stem cell: a target to eradicate cancer.
    Shuo Zhang, Neng Zhu, Hong Fang Li, Jia Gu, Chan Juan Zhang, Duan Fang Liao, Li Qin.
      Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem cell properties that sustain cancers, which may be responsible for cancer metastasis or recurrence. Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in the plasma membrane that mediate various intracellular signaling. The occurrence and progression of cancer are closely related to lipid rafts. Emerging evidence indicates that lipid raft levels are significantly enriched in CSCs compared to cancer cells and that most CSC markers such as CD24, CD44, and CD133 are located in lipid rafts. Furthermore, lipid rafts play an essential role in CSCs, specifically in CSC self-renewal, epithelial-mesenchymal transition, drug resistance, and CSC niche. Therefore, lipid rafts are critical regulatory platforms for CSCs and promising therapeutic targets for cancer therapy.
    Keywords:  Cancer; Cancer stem cell; Cancer stem cell niche; Drug resistance; Epithelial-mesenchymal transition; Lipid raft; Self-renewal
    DOI:  https://doi.org/10.1186/s13287-022-03111-8
  7. Cancer Cell. 2022 Aug 26. pii: S1535-6108(22)00383-X. [Epub ahead of print]
    Cellular hierarchies predict drug response in acute myeloid leukemia.
    Simon Raffel, Lars Velten, Simon Haas.
      In a recent Nature Medicine study, Zeng and colleagues integrate both genomic and stem cell models of acute myeloid leukemia (AML) by deconvoluting cellular hierarchies of more than 1,000 AML samples. This work introduces a framework capable of predicting drug responses to targeted therapies in future clinical trials.
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.019
  8. Leukemia. 2022 Aug 29.
    A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure.
    Monika M Kutyna, Chung Hoow Kok, Yoon Lim, Elizabeth Ngoc Hoa Tran, David Campbell, Sharon Paton, Chloe Thompson-Peach, Kelly Lim, Dimitrios Cakouros, Agnes Arthur, Timothy Hughes, Sharad Kumar, Daniel Thomas, Stan Gronthos, Devendra K Hiwase.
      Therapy-related myeloid neoplasm (tMN) is considered a direct consequence of DNA damage in hematopoietic stem cells. Despite increasing recognition that altered stroma can also drive leukemogenesis, the functional biology of the tMN microenvironment remains unknown. We performed multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterization of bone marrow stromal cells from tMN patients. Critically, we also compared (i) patients with myeloid neoplasm and another cancer but without cytotoxic exposure, (ii) typical primary myeloid neoplasm, and (iii) age-matched controls to decipher the microenvironmental changes induced by cytotoxics vs. neoplasia. Strikingly, tMN exhibited a profoundly senescent phenotype with induction of CDKN1A and β-Galactosidase, defective phenotype, and proliferation. Moreover, tMN stroma showed delayed DNA repair and defective adipogenesis. Despite their dormant state, tMN stromal cells were metabolically highly active with a switch toward glycolysis and secreted multiple pro-inflammatory cytokines indicative of a senescent-secretory phenotype that inhibited adipogenesis. Critically, senolytics not only eliminated dormant cells, but also restored adipogenesis. Finally, sequential patient sampling showed senescence phenotypes are induced within months of cytotoxic exposure, well prior to the onset of secondary cancer. Our data underscores a role of senescence in the pathogenesis of tMN and provide a valuable resource for future therapeutics.
    DOI:  https://doi.org/10.1038/s41375-022-01686-y
  9. Blood Adv. 2022 Aug 31. pii: bloodadvances.2022007528. [Epub ahead of print]
    Impact of mesenchymal stromal cell-derived vesicular cargo on B-cell acute lymphoblastic leukemia progression.
    Christina Karantanou, Valentina R Minciacchi, Rahul Kumar, Costanza Zanetti, Jimena Bravo, Raquel S Pereira, Georg Tascher, Tobias Tertel, Adriana Covarrubias-Pinto, Katrin Bankov, Lisa-Marie Pfeffermann, Halvard Bonig, Paola Divieti-Pajevic, David G McEwan, Bernd Giebel, Christian Münch, Ivan Dikic, Daniela S Krause.
      Leukemia cells reciprocally interact with their surrounding bone marrow microenvironment (BMM), rendering it hospitable to leukemia cell survival, for instance by release of small extracellular vesicles (sEV). In converse, we show here, that BMM-deficiency of pleckstrin homology domain family M member 1 (PLEKHM1), which serves as a hub between fusion and secretion of intracellular vesicles and is important for vesicular secretion in osteoclasts, accelerates murine BCR-ABL1+ B-cell acute lymphoblastic leukemia (B-ALL) via regulation of the cargo of sEV released by BMM-derived mesenchymal stromal cells (MSC). PLEKHM1-deficient MSC and their sEV carry increased amounts of syntenin and syndecan-1, resulting in a more immature B cell phenotype and increased number/function of leukemia-initiating cells (LIC) via focal adhesion kinase (FAK) and AKT signaling in B-ALL cells. Ex vivo pretreatment of LIC with sEV derived from PLEKHM1-deficient MSC led to a strong trend towards acceleration of murine and human BCR-ABL1+ B-ALL. In turn, inflammatory mediators such as recombinant or B-ALL-cell derived tumor necrosis factor (TNF) α or interleukin (IL)-1β condition murine and human MSC in vitro, decreasing PLEKHM1, while increasing syntenin and syndecan-1 in MSC, thereby perpetuating the sEV-associated circuit. Consistently, human trephine biopsies of patients with B-ALL showed a reduced percentage of PLEKHM1+ MSC. In summary, our data reveal an important role of BMM-derived sEV for driving specifically BCR-ABL1+ B-ALL, possibly contributing to its worse prognosis compared to BCR-ABL1- B-ALL, and suggest that secretion of inflammatory cytokines by cancer cells in general may similarly modulate the tumor microenvironment.
    DOI:  https://doi.org/10.1182/bloodadvances.2022007528
  10. Drug Metab Rev. 2022 Aug 27. 1-15
    Targeting endothelial cell metabolism in cancerous microenvironment: a new approach for anti-angiogenic therapy.
    Parisa Mohammadi, Reza Yarani, Azam Rahimpour, Fatemeh Ranjbarnejad, Joana Mendes Lopes de Melo, Kamran Mansouri.
      Anti-angiogenic therapy is a practical approach to managing diseases with increased angiogenesis, such as cancer, maculopathies, and retinopathies. Considering the fundamental gaps in the knowledge of the vital pathways involved in angiogenesis and its inhibition and the insufficient efficiency of existing angiogenesis inhibitors, there is an increasing focus on the emergence of new therapeutic strategies aimed at inhibiting pathological angiogenesis. Angiogenesis is forming a new vascular network from existing vessels; endothelial cells (ECs), vascular lining cells, are the main actors of angiogenesis in physiological or pathological conditions. Switching from a quiescent state to a highly migratory and proliferative state during new vessel formation called "angiogenic switch" is driven by a "metabolic switch" in ECs, angiogenic growth factors, and other signals. As the characteristics of ECs change by altering the surrounding environment, they appear to have a different metabolism in a tumor microenvironment (TME). Therefore, pathological angiogenesis can be inhibited by targeting metabolic pathways. In the current review, we aim to discuss the EC metabolic pathways under normal and TME conditions to verify the suitability of targeting them with novel therapies.
    Keywords:  Tumor microenvironment; angiogenesis inhibitors; metabolic switch; metabolism; targeted therapies; tumor endothelial cell
    DOI:  https://doi.org/10.1080/03602532.2022.2116033
  11. Front Immunol. 2022 ;13 937327
    A promising antitumor method: Targeting CSC with immune cells modified with CAR.
    Binjie Huang, Lele Miao, Jie Liu, Jiaxing Zhang, Yumin Li.
      Tumors pose a great threat to human health; as a subgroup of tumor cells, cancer stem cells (CSCs) contribute to the genesis, development, metastasis, and recurrence of tumors because of their enhanced proliferation and multidirectional differentiation. Thus, a critical step in tumor treatment is to inhibit CSCs. Researchers have proposed many methods to inhibit or reduce CSCs, including monoclonal antibodies targeting specific surface molecules of CSCs, signal pathway inhibitors, and energy metabolic enzyme inhibitors and inducing differentiation therapy. Additionally, immunotherapy with immune cells engineered with a chimeric antigen receptor (CAR) showed favorable results. However, there are few comprehensive reviews in this area. In this review, we summarize the recent CSC targets used for CSC inhibition and the different immune effector cells (T cells, natural killer (NK) cells, and macrophages) which are engineered with CAR used for CSC therapy. Finally, we list the main challenges and options in targeting CSC with CAR-based immunotherapy. The design targeting two tumor antigens (one CSC antigen and one mature common tumor antigen) should be more reasonable and practical; meanwhile, we highlight the potential of CAR-NK in tumor treatment.
    Keywords:  CAR; CAR-NK; CSC; immunotherapy; targeted strategy
    DOI:  https://doi.org/10.3389/fimmu.2022.937327
  12. Trends Cell Biol. 2022 Aug 18. pii: S0962-8924(22)00191-X. [Epub ahead of print]
    Mitochondria in cancer: clean windmills or stressed tinkerers?
    Dario C Altieri.
      There is now a consensus that mitochondria are important tumor drivers, sophisticated biological machines that can engender a panoply of key disease traits. How this happens, however, is still mostly elusive. The opinion presented here is that what cancer exploits are not the normal mitochondria of oxygenated and nutrient-replete tissues, but the unfit, damaged, and dysfunctional organelles generated by the hostile environment of tumor growth. These 'ghost' mitochondria survive quality control and thwart cell death to relay multiple comprehensive 'danger signals' of metabolic starvation, cellular stress, and reprogrammed gene expression. The result is a new, treacherous cellular phenotype, proliferatively quiescent but highly motile, that enables tumor cell escape from a threatening environment and colonization of distant, more favorable sites (metastasis).
    Keywords:  Mic60; metabolism; metastasis; mitochondria; tumor plasticity
    DOI:  https://doi.org/10.1016/j.tcb.2022.08.001
  13. Cell Biol Int. 2022 Aug 28.
    Anoikis in cancer: The role of lipid signaling.
    Mortaza Raeisi, Mojtaba Zehtabi, Kobra Velaei, Parisa Fayyazpour, Negar Aghaei, Amir Mehdizadeh.
      Malignantly transformed cells must alter their metabolic status to stay viable in a harsh microenvironment and maintain their ability to invade and spread. Anoikis, a specific detachment-related form of apoptotic cell death, is a potential barrier to cancer cell metastasis. Several molecular/pathway alterations have been implicated in preventing anoikis in metastatic cancers. Specific alterations in the lipid metabolism machinery (such as an increase in fatty acid uptake and synthesis) and modifications in the carbohydrate and amino acid metabolism are partially identified mechanisms associated with the anoikis resistance in various types of cancers, among other survival benefits. Following a summary of the molecular basis of the anoikis pathway, its resistance mechanisms, and the fundamentals of lipid metabolism in cancer, this article aims to elucidate the impact of lipid metabolism deviations recruited by cancer cells to escape anoikis.
    Keywords:  anoikis; fatty acids; lipogenesis; malignancy; metastasis
    DOI:  https://doi.org/10.1002/cbin.11896
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