bims-almceb 2022-05-01 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022‒05‒01
eleven papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

Human acute myeloid leukemia stem cells: evolution of concept.
Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.
JMJD1C-regulated lipid synthesis contributes to the maintenance of MLL-rearranged acute myeloid leukemia.
Current status of cancer starvation therapy.
Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia.
Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.
Non-metabolic functions of Pyruvate kinase M2: PKM2 in tumorigenesis and therapy resistance.
CD36-Mediated Fatty Acid Oxidation in Hematopoietic Stem Cells Is a Novel Mechanism of Emergency Hematopoiesis in Response to Infection.
Interleukin-4 treatment reduces leukemia burden in acute myeloid leukemia.
Mechanisms of cancer stem cells drug resistance and the pivotal role of HMGA2.
Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.

Blood Res. 2022 Apr 30. 57(S1): 67-74

Human acute myeloid leukemia stem cells: evolution of concept.

Dong-Yeop Shin.

  The history of human acute myeloid leukemia stem cells (AMLSCs) began in a seminal study performed by Lapidot and Dick, proving that only CD34+CD38- human primary acute myeloid leukemia (AML) cells can repopulate in severe combined immunodeficient mice. The concept of leukemic stem cells (LSCs) has impeded a huge change in the treatment strategy against AML from killing proliferating leukemic cells to eradicating quiescent/dormant LSCs. As next-generation sequencing technologies have developed, multiple and recurrent genetic mutations have been discovered in large cohorts of patients with AML, and the updated understanding of leukemogenesis has improved the old concept of LSC to a revised version of a serial developmental model of LSC; that is, pre-LSCs are generated as seeds by the first hit on epigenetic regulators, and then, leukemia-initiating LSCs emerge from seeds by the second hits on genes involved in transcription and signaling. Dreams for universal and targetable AMLSC biomarker sparing healthy hematopoietic stem cells have weakened after the confrontation of significant heterogeneity of AMLSCs from genomic and immunophenotypic viewpoints. However, there is still hope for effective targets for AMLSCs since there is evidence that grouped gene signatures, such as 17-gene LSC score, and common epigenetic signatures, such as HOXA clusters, independent of various gene mutations, exist. Recently, the LSC niche in the bone marrow has been actively investigated and has expanded our knowledge of the physiology and vulnerability of AMLSCs. Presently, an applicable treatment that always works in AMLSCs is lacking. However, we will find a way, we always have.

Keywords:  Acute myeloid leukemia; Acute myeloid leukemia stem cell; Leukemic stem cell; Pre-leukemic stem cell

DOI:  https://doi.org/10.5045/br.2022.2021221
Cell Rep. 2022 Apr 26. pii: S2211-1247(22)00516-2. [Epub ahead of print]39(4): 110752

Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.

Vivian Morris, Dahai Wang, Zhiheng Li, William Marion, Travis Hughes, Patricia Sousa, Taku Harada, Shannan Ho Sui, Sergey Naumenko, Jérémie Kalfon, Prerana Sensharma, Marcelo Falchetti, Renan Vinicius da Silva, Tito Candelli, Pauline Schneider, Thanasis Margaritis, Frank C P Holstege, Yana Pikman, Marian Harris, Ronald W Stam, Stuart H Orkin, Angela N Koehler, Alex K Shalek, Trista E North, Maxim Pimkin, George Q Daley, Edroaldo Lummertz da Rocha, R Grant Rowe.

  High-risk forms of B-acute lymphoblastic leukemia (B-ALL) remain a therapeutic challenge. Leukemia-initiating cells (LICs) self-renew and spark relapse and therefore have been the subject of intensive investigation; however, the properties of LICs in high-risk B-ALL are not well understood. Here, we use single-cell transcriptomics and quantitative xenotransplantation to understand LICs in MLL-rearranged (MLL-r) B-ALL. Compared with reported LIC frequencies in acute myeloid leukemia (AML), engraftable LICs in MLL-r B-ALL are abundant. Although we find that multipotent, self-renewing LICs are enriched among phenotypically undifferentiated B-ALL cells, LICs with the capacity to replenish the leukemic cellular diversity can emerge from more mature fractions. While inhibiting oxidative phosphorylation blunts blast proliferation, this intervention promotes LIC emergence. Conversely, inhibiting hypoxia and glycolysis impairs MLL-r B-ALL LICs, providing a therapeutic benefit in xenotransplantation systems. These findings provide insight into the aggressive nature of MLL-r B-ALL and provide a rationale for therapeutic targeting of hypoxia and glycolysis.

Keywords:  CP: Cancer; CP: Metabolism; leukemia; metabolism; stem cell

DOI:  https://doi.org/10.1016/j.celrep.2022.110752
Leuk Lymphoma. 2022 Apr 25. 1-12

JMJD1C-regulated lipid synthesis contributes to the maintenance of MLL-rearranged acute myeloid leukemia.

Daoxin Qi, Jialing Wang, Yao Zhao, Yong Yang, Yishu Wang, Haihua Wang, Lin Wang, Zhanju Wang, Xin Xu, Zhenbo Hu.

  Mixed Lineage Leukemia rearranged acute myeloid leukemia (MLLr AML) predicts a poor prognosis. Histone demethylase JMJD1C is a potential druggable target of MLLr AML. However, little is known about how JMJD1C contributes to MLLr AML. Here we found that JMJD1C regulates lipid synthesis-associated genes including FADS2, SCD in MLLr AML cells. Lipid synthesis-associated protein FABP5 was identified as a specific interacting protein of JMJD1C and binds to the jumonji domain of JMJD1C. FABP5 also regulates JMJD1C mRNA and protein expression. JDI-10, a small molecular inhibitor of JMJD1C identified by us, represses MLLr AML cells, induces apoptosis, and decreases JMJD1C-regulated lipid synthesis genes. Moreover, JDI-10 mediated suppression of MLLr AML cells can be rescued by palmitic acid, oleic acid, or recombinant FABP5. In summary, we identified that JMJD1C-regulated lipid synthesis contributes to the maintenance of MLLr AML. Lipid synthesis repression may represent a new direction for the treatment of MLLr AML.

Keywords:  JMJD1C; Mixed lineage leukemia rearranged acute myeloid leukemia (MLLr AML); lipid synthesis; small molecular inhibitors

DOI:  https://doi.org/10.1080/10428194.2022.2068004
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Jan 25. 50(7): 1-11

Current status of cancer starvation therapy.

Jianyi Li, Dandan Tong, Junsheng Lin.

  Conventional therapies for malignant tumors have limitations and disadvantages. In recent years, the cancer starvation therapy has emerged which intends to deprive cancer cells of nutritional supply. There are several approaches to"starve" cancer cells: to intervene tumor angiogenesis by targeted inhibition of angiogenic factors or their receptors and integrins; to block the blood supply of cancer cells by embolizing or compressing blood vessels; to intervene metabolic process of cancer cells by inhibition of the signal pathways of mitochondrial serine-glycine-one earbon metabolism, glycolysis and amino acid metabolism; cancer starvation therapy can be employed with oxidation therapy, chemotherapy, sonodynamic therapy, anti-autophagy therapy or other therapies to achieve synergistic effects. This article reviews the research progress of cancer starvation therapy in recent years and discusses the existing problems.

Keywords:  Anti-angiogenesis; Neoplasms; Review; Starvation therapy; Synergistic therapy; Tumor metabolism

DOI:  https://doi.org/10.3724/zdxbyxb-2021-0297
Leukemia. 2022 Apr 23.

Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia.

Alec W Stranahan, Iryna Berezniuk, Sohini Chakraborty, Faye Feller, Mona Khalaj, Christopher Y Park.

Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following standard-of-care induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor. Therefore, we sought to identify resistance genes to induction therapy in AML and elucidated ALOX5 as a novel mediator of resistance to anthracycline-based therapy. ALOX5 is transcriptionally upregulated in AML patient blasts in comparison to normal hematopoietic stem/progenitor cells (HSPCs) and ALOX5 mRNA, and protein expression is increased in response to induction therapy. In vitro, and in vivo genetic, and pharmacologic perturbation studies confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, and its loss does not significantly affect the function of normal HSPCs. ALOX5 mediates resistance to daunorubicin (DNR) and promotes AML cell survival and maintenance through its leukotriene (LT) synthetic capacity, specifically via modulating the synthesis of LTB4 and its binding to LTB receptor (BLTR). Our study reveals a previously unrecognized role of LTs in AML pathogenesis and chemoresistance, whereby inhibition of ALOX5 mediated LTB4 synthesis and function could be combined with standard chemotherapy, to enhance the overall therapeutic efficacy in AML.

DOI: https://doi.org/10.1038/s41375-022-01579-0
Acta Biomater. 2022 Apr 20. pii: S1742-7061(22)00231-8. [Epub ahead of print]

Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.

Xiangyu Meng, Zhuoxuan Lu, Qingyu Lv, Yongqiang Jiang, Liming Zhang, Zhifei Wang.

  Cancer cells rely on glycolysis to support a high proliferation rate. Metformin (Met) is a promising drug for tumor treatment that targets hexokinase 2 (HK2) to block the glycolytic process, thereby further disrupting the metabolism of cancer cells. Herein, an intelligent nanomedicine based on glucose deprivation and glycolysis inhibition is creatively constructed for enhanced cancer synergistic treatment. In brief, Met and glucose oxidase (GOx) was encapsulated into histidine/zeolitic imidazolate framework-8 (His/ZIF-8), which was followed by coating with Arg-Gly-Asp (RGD) peptides to obtain the desired nanomedicine (Met/GOx@His/ZIF-8∼RGD). This smart nanomedicine presents the controllable Met and GOx release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. According to in vitro and in vivo assays, the combination of glycolysis inhibition and starvation therapy demonstrates efficient cancer cells growth suppression and superior antitumor properties compared to the Met-based or GOx-mediated monotherapy. This work provides an advanced therapeutic strategy via disrupting cellular metabolism against cancer. STATEMENT OF SIGNIFICANCE: The obtained nanomedicine (Met/GOx@His/ZIF-8∼RGD) presents the controllable Met and glucose oxidase (GOx) release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. The combination of glycolysis inhibition and starvation therapy demonstrate the efficient suppression of cancer cells growth and the superior antitumor properties when compared to the Met-based or GOx-mediated monotherapy.

Keywords:  Metformin; glycolysis inhibition; modified zeolitic imidazolate framework-8; starvation therapy; tumor metabolism

DOI:  https://doi.org/10.1016/j.actbio.2022.04.022
Neoplasma. 2022 Apr 26. pii: 220119N77. [Epub ahead of print]

Non-metabolic functions of Pyruvate kinase M2: PKM2 in tumorigenesis and therapy resistance.

Mustafa İlhan.

Cancer is the disease of uncontrollably dividing cells in the body. As cancer cells proliferate at higher rates, they need more energy in a short time necessitating deregulation of energy-generating pathways for their benefit. Although oxidative phosphorylation generates more energy from a glucose molecule, cancer cells have a tendency to enhance aerobic glycolysis by consuming more glucose and producing lactate as a by-product even if oxygen is present. In addition to the generation of rapid energy to fulfill their increasing demands, this strategy also provides the use of glucose metabolites such as lactate as a source for the synthesis of anabolic molecules, such as nucleotides, amino acids, and lipids during the rapid phase of the proliferation. Pyruvate kinase M2 (PKM2) is an isoform of pyruvate kinase, which mediates the balancing of energy generation mechanisms during the anabolic and catabolic events. Due to its vital role in glycolysis, PKM2 has been investigated to target cancer cell metabolism for several years. However, recent studies demonstrate that PKM2 may also promote cancer progression by regulating core steps in metastasis such as migration, angiogenesis, and stemness. Of note, it is estimated that 90% of cancer-related deaths are due to metastasis. This review is intended to summarize the recent advances in the non-metabolic roles of PKM2 in cancer progression and to indicate its potential uses for the development of new treatment strategies.

DOI: https://doi.org/10.4149/neo_2022_220119N77
Immunometabolism. 2022 ;pii: e220008. [Epub ahead of print]4(2):

CD36-Mediated Fatty Acid Oxidation in Hematopoietic Stem Cells Is a Novel Mechanism of Emergency Hematopoiesis in Response to Infection.

Maria Maryanovich, Keisuke Ito.

  Hematopoietic homeostasis depends on the close regulation of hematopoietic stem cell (HSC) activity in the bone marrow. Quiescence and activation in response to stress, among other changes in state, are mediated by shifts in HSC metabolic activity. Although HSC steady-state metabolism is well established, the mechanisms driving HSC activation, proliferation, and differentiation in response to stress remain poorly understood. Here we discuss a study by Mistry et al. that describes a novel metabolic mechanism that fuels HSC activation and expansion. The authors show that to meet their metabolic needs in response to infection, hematopoietic stem and progenitor cells uptake free fatty acids from their microenvironment via CD36 to fuel fatty acid oxidation. These exciting findings suggest that in the context of infection, HSCs undergo a metabolic shift toward fatty acid metabolism that drives emergency hematopoiesis and raise questions about the role of the microenvironment in this process.

Keywords:  CD36; fatty-acid oxidation; hematopoiesis; hematopoietic stem cells; infection; oxidative phosphorylation

DOI:  https://doi.org/10.20900/immunometab20220008
FASEB J. 2022 May;36(5): e22328

Interleukin-4 treatment reduces leukemia burden in acute myeloid leukemia.

Fenghua Qian, Brooke E Arner, Kathleen M Kelly, Charyguly Annageldiyev, Arati Sharma, David F Claxton, Robert F Paulson, K Sandeep Prabhu.

  Interleukin-4 (IL-4) is a signature cytokine pivotal in Type 2 helper T cell (Th2) immune response, particularly in allergy and hypersensitivity. Interestingly, IL-4 increases endogenous levels of prostaglandin D2 (PGD2 ) and its metabolites, Δ12 -prostaglandin J2 (Δ12 -PGJ2 ) and 15-deoxy-Δ12,14 -prostaglandin J2 (15d-PGJ2 ), collectively called cyclopentenone PGs (CyPGs). However, the therapeutic role of IL-4 in hematologic malignancies remains unclear. Here, we employed a murine model of acute myeloid leukemia (AML), where human MLL-AF9 fusion oncoprotein was expressed in hematopoietic progenitor cells, to test the effect of IL-4 treatment in vivo. Daily intraperitoneal treatment with IL-4 at 60 µg/kg/d significantly alleviated the severity of AML, as seen by decreased leukemia-initiating cells (LICs). The effect of IL-4 was mediated, in part, by the enhanced expression of hematopoietic- PGD2 synthase (H-PGDS) to effect endogenous production of CyPGs, through autocrine and paracrine signaling mechanisms. Similar results were seen with patient-derived AML cells cultured ex vivo with IL-4. Use of GW9662, a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, suggested endogenous CyPGs-PPARγ axis mediated p53-dependent apoptosis of LICs by IL-4. Taken together, our results reveal a beneficial role of IL-4 treatment in AML suggesting a potential therapeutic regimen worthy of clinical trials in patients with AML.

Keywords:  AML; H-PGDS; IL-4; PPARγ; prostaglandin

DOI:  https://doi.org/10.1096/fj.202200251R
Pathol Res Pract. 2022 Apr 19. pii: S0344-0338(22)00150-9. [Epub ahead of print]234 153906

Mechanisms of cancer stem cells drug resistance and the pivotal role of HMGA2.

Huldani Huldani, Saade Abdalkareem Jasim, Klunko Nataliya Sergeenva, Dmitry Olegovich Bokov, Walid Kamal Abdelbasset, Rustam Turakulov, Moaed E Al-Gazally, Behnam Ahmadzadeh, Zanko Hassan Jawhar, Homayoon Siahmansouri.

  Nowadays, the focus of researchers is on perceiving the heterogeneity observed in a tumor. The researchers studied the role of a specific subset of cancer cells with high resistance to traditional treatments, recurrence, and unregulated metastasis. This small population of tumor cells that have stem-cell-like specifications was named Cancer Stem Cells (CSCs). The unique features that distinguish this type of cancer cell are self-renewing, generating clones of the tumor, plasticity, recurrence, and resistance to therapies. There are various mechanisms that contribute to the drug resistance of CSCs, such as CSCs markers, Epithelial mesenchymal transition, hypoxia, other cells, inflammation, and signaling pathways. Recent investigations have revealed the primary role of HMGA2 in the development and invasion of cancer cells. Importantly, HMGA2 also plays a key role in resistance to treatment through their function in the drug resistance mechanisms of CSCs and challenge it. Therefore, a deep understanding of this issue can provide a clearer perspective for researchers in the face of this problem.

Keywords:  Cancer stem cells; Chemo-resistance; Drug resistance; HMGA2

DOI:  https://doi.org/10.1016/j.prp.2022.153906
Nat Chem Biol. 2022 May;18(5): 461-469

Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.

Michael P Murphy, Edward T Chouchani.

Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.

DOI: https://doi.org/10.1038/s41589-022-01004-8