bims-almceb 2021-07-04 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–07–04
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Autophagy a Close Relative of AML Biology.
Acute Myeloid Leukemia Mutations and Future Mechanistic Target to Overcome Resistance.
Melatonin inhibits lung cancer development by reversing the Warburg effect via stimulating the SIRT3/PDH axis.
A Regulatory Loop Involving Notch and Wnt Signaling Maintains Leukemia Stem Cells in T-Cell Acute Lymphoblastic Leukemia.
Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update.
Neonatal heel prick mass spectrometry identifies metabolic predictors of AML latency.
Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia.
Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.
Mitochondrial Function Are Disturbed in the Presence of the Anticancer Drug, 3-Bromopyruvate.
FATTY ACID SYNTHESIS IS REQUIRED FOR BREAST CANCER BRAIN METASTASIS.
Responsiveness to Hedgehog Pathway Inhibitors in T-Cell Acute Lymphoblastic Leukemia Cells Is Highly Dependent on 5'AMP-Activated Kinase Inactivation.
Hampering Stromal Cells in the Tumor Microenvironment as a Therapeutic Strategy to Destem Cancer Stem Cells.

Biology (Basel). 2021 Jun 18. pii: 552. [Epub ahead of print]10(6):

Autophagy a Close Relative of AML Biology.

Carine Joffre, Charlotte Ducau, Laura Poillet-Perez, Charly Courdy, Véronique Mansat-De Mas.

  Autophagy, which literally means "eat yourself", is more than just a lysosomal degradation pathway. It is a well-known regulator of cellular metabolism and a mechanism implicated in tumor initiation/progression and therapeutic resistance in many cancers. However, whether autophagy acts as a tumor suppressor or promoter is still a matter of debate. In acute myeloid leukemia (AML), it is now proven that autophagy supports cell proliferation in vitro and leukemic progression in vivo. Mitophagy, the specific degradation of mitochondria through autophagy, was recently shown to be required for leukemic stem cell functions and survival, highlighting the prominent role of this selective autophagy in leukemia initiation and progression. Moreover, autophagy in AML sustains fatty acid oxidation through lipophagy to support mitochondrial oxidative phosphorylation (OxPHOS), a hallmark of chemotherapy-resistant cells. Nevertheless, in the context of therapy, in AML, as well as in other cancers, autophagy could be either cytoprotective or cytotoxic, depending on the drugs used. This review summarizes the recent findings that mechanistically show how autophagy favors leukemic transformation of normal hematopoietic stem cells, as well as AML progression and also recapitulates its ambivalent role in resistance to chemotherapies and targeted therapies.

Keywords:  AML; autophagy; hematopoiesis; mitophagy; therapy

DOI:  https://doi.org/10.3390/biology10060552
Curr Treat Options Oncol. 2021 Jul 02. 22(9): 76

Acute Myeloid Leukemia Mutations and Future Mechanistic Target to Overcome Resistance.

Rehan Uddin, Noureldian H E Darwish, Shaker A Mousa.

   OPINION STATEMENT: Cytogenetics and mutation identification in acute myeloid leukemia have allowed for more targeted therapy. Many therapies have been approved by the FDA in the last 3 years including gilteritinib and azacitidine but the overall survival has remained stagnant at 25%. The inability to achieve complete remission was related to the residual leukemic stem cells (LSCs). Thus, the relationship between bone marrow niche and LSCs must be further explored to prevent treatment relapse/resistance. The development of immunotherapy and nanotechnology may play a role in future therapy to achieve the complete remission. Nano-encapsulation of drugs can improve drugs' bioavailability, help drugs evade resistance, and provide combination therapy directly to the cancer cells. Studies indicate targeting surface antigens such as CLL1 and CD123 using chimeric antibody receptor T cells can improve survival outcomes. Finally, new discoveries indicate that inhibiting integrin αvβ3 and acid ceramidase may prove to be efficacious.

Keywords:  Acid ceramidase; Acute myeloid leukemia resistance; BCL-2; Bone marrow microenvironment; CAR T; FLT3; Hedgehog; Immunotherapy; Nanotechnology

DOI:  https://doi.org/10.1007/s11864-021-00880-x
J Pineal Res. 2021 Jul 02. e12755

Melatonin inhibits lung cancer development by reversing the Warburg effect via stimulating the SIRT3/PDH axis.

Xiangyun Chen, Bingjie Hao, Dan Li, Russel J Reiter, Yidong Bai, Baigenzhin Abay, Guojie Chen, Shumeng Lin, Tiansheng Zheng, Yanbei Ren, Xiao Xu, Ming Li, Lihong Fan.

  Recently, the morbidity and mortality from lung cancer have continued to increase. Mitochondrial dysfunction plays a key role in apoptosis, proliferation and the bioenergetic reprogramming of cancer cells, especially for energy metabolism. Herein, we investigated the ability of melatonin (MLT) to influence lung cancer growth and explored the association between mitochondrial function and the progression of lung tumors. The deacetylase, sirtuin 3 (Sirt3), is a pivotal player in maintenance of mitochondrial function; among participating in ATP production by regulating the acetylone and pyruvate dehydrogenase complex (PDH). We initially found that MLT inhibited lung cancer growth in the Lewis mouse model. Similarly, we observed that MLT inhibited the proliferation of lung cancer cells (A549, PC9 and LLC cells), and the underlying mechanism of MLT was related to reprogramming cancer cell metabolism, accompanied by a shift from cytosolic aerobic glycolysis to oxidative phosphorylation (OXPHOS). These changes were accompanied by higher ATP production, an elevated ATP production-coupled oxygen consumption rate (QCR), higher ROS levels, higher mito-ROS levels and lower lactic acid secretion. Additionally, we observed that MLT improved mitochondrial membrane potential and the activities of complexes Ⅰ and Ⅳ of the electron transport chain. Importantly, we also found and verified that the foregoing changes resulted from activation of Sirt3 and PDH. As a result of these changes, MLT significantly enhanced mitochondrial energy metabolism to reverse the Warburg effect via increasing PDH activity via stimulation of Sirt3. Collectively, these findings suggest the potential use of melatonin as an anti-lung cancer therapy and provide a mechanistic basis for this proposal.

Keywords:  Lung cancer; Warburg effect; melatonin; mitochondria; oxidative phosphorylation; pyruvate dehydrogenase complex; sirtuin 3

DOI:  https://doi.org/10.1111/jpi.12755
Front Cell Dev Biol. 2021 ;9 678544

A Regulatory Loop Involving Notch and Wnt Signaling Maintains Leukemia Stem Cells in T-Cell Acute Lymphoblastic Leukemia.

Ling Zhang, Jieying Wu, Yashu Feng, Bijay Khadka, Zhigang Fang, Jiaming Gu, Baoqiang Tang, Ruozhi Xiao, Guangjin Pan, Jia-Jun Liu.

  Leukemia-initiating cells play critical role in relapse, resistance to therapies and metastases but the mechanism remains largely elusive. We report that β-catenin is over-expressed in almost all T-ALL patients and flow sorted β-cateninhigh fractions are highly resistant to therapy, leading to liver metastases in nude mice as well as dysregulated lncRNAs. Pharmacological inhibition through XAV-939 as well as si-RNA mediated inhibition of β-catenin is initially effective in re-sensitization to therapy, however, prolonged inhibition shifts dependency from β-catenin to Notch signaling, with particularly high levels of receptors Notch 1 and Notch 2. The results are verifiable in a cohort of T-ALL patients comprising of responders vs. those who have progressed, with β-catenin, Notch 1 and Notch 2 elevated in progressed patients. Further, in patients-derived cells, silencing of Notch 1 or Notch 2 does not counter resistance to β-catenin inhibition, rather pharmacological pan-Notch inhibition is needed to overcome resistance and its effect on in vitro tumor sphere formations as well as in vivo liver metastases. Thus, wnt and Notch signaling are part of a regulatory loop mutually compensating for each other in T-ALL, while ensuring the maintenance of stem cell phenotype.

Keywords:  T-cell acute lymphoblastic leukemia; Wnt; cancer stem cells; notch; relapse

DOI:  https://doi.org/10.3389/fcell.2021.678544
Int J Mol Sci. 2021 Jun 19. pii: 6587. [Epub ahead of print]22(12):

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update.

Philippe Icard, Antoine Coquerel, Zherui Wu, Joseph Gligorov, David Fuks, Ludovic Fournel, Hubert Lincet, Luca Simula.

  Citrate plays a central role in cancer cells' metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies.

Keywords:  ACLY; Warburg effect; cancer cells; citrate; resistance to therapies

DOI:  https://doi.org/10.3390/ijms22126587
Leuk Res. 2021 Jun 15. pii: S0145-2126(21)00145-4. [Epub ahead of print]109 106644

Neonatal heel prick mass spectrometry identifies metabolic predictors of AML latency.

Kelly Lim, Chloe Thompson-Peach, Daniel Thomas.

  Ongoing research efforts that consider cancer as a disease of dramatically altered cellular metabolism have accelerated interest in snapshot metabolomics in various human tissues. In this issue of Leukemia Research, Petrick et al performed metabolomic analysis on newborn blood spots and found a number of unexpected ceramide and sphingolipid compounds that may play a role in the development and latency of pediatric acute myeloid leukemia (AML). The chemical complexity and range of cellular metabolites massively exceeds the relatively limited building blocks of the transcriptome or the proteome and has high potential to find novel leukemia-specific macromolecular synthesis pathways, metabolic vulnerabilities and biomarkers.

Keywords:  AML; Dried blood spots; Heel prick; Leukemia; Mass spectrometry; Metabolic predictors; Metabolomics

DOI:  https://doi.org/10.1016/j.leukres.2021.106644
Antioxidants (Basel). 2021 Jun 15. pii: 956. [Epub ahead of print]10(6):

Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia.

Zhengqi Wang, Tian Mi, Heath L Bradley, Jonathan Metts, Himalee Sabnis, Wandi Zhu, Jack Arbiser, Kevin D Bunting.

  Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to resistance-conferring mutations. Likewise, targeting downstream signaling pathways has been difficult. Recent success in the development of synergistic combinations has provided new hope for refractory AML patients. While generally not efficacious as monotherapy, BH3 mimetics are very effective in combination with chemotherapy agents. With this in mind, we further explored novel BH3 mimetic drug combinations and showed that pimozide cooperates with mTOR inhibitors and BH3 mimetics in AML cells. The three-drug combination was able to reach cells that were not as responsive to single or double drug combinations. In Flt3-internal tandem duplication (ITD)-positive cells, we previously showed pimozide to be highly effective when combined with imipramine blue (IB). Here, we show that Flt3-ITD+ cells are sensitive to an IB-induced dynamin 1-like (Drp1)-p38-ROS pathway. Pimozide contributes important calcium channel blocker activity converging with IB on mitochondrial oxidative metabolism. Overall, these data support the concept that antioxidants are a double-edged sword. Rationally designed combination therapies have significant promise for further pre-clinical development and may ultimately lead to improved responses.

Keywords:  BH3 mimetic; Flt3-internal tandem duplication; acute myeloid leukemia; mTOR inhibitor; mitoSox; reactive oxygen species; repurposed drugs

DOI:  https://doi.org/10.3390/antiox10060956
Leukemia. 2021 Jun 30.

Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.

Giorgia Simonetti, Carlo Mengucci, Antonella Padella, Eugenio Fonzi, Gianfranco Picone, Claudio Delpino, Jacopo Nanni, Rossella De Tommaso, Eugenia Franchini, Cristina Papayannidis, Giovanni Marconi, Martina Pazzaglia, Margherita Perricone, Emanuela Scarpi, Maria Chiara Fontana, Samantha Bruno, Michela Tebaldi, Anna Ferrari, Maria Teresa Bochicchio, Andrea Ghelli Luserna Di Rorà, Martina Ghetti, Roberta Napolitano, Annalisa Astolfi, Carmen Baldazzi, Viviana Guadagnuolo, Emanuela Ottaviani, Ilaria Iacobucci, Michele Cavo, Gastone Castellani, Torsten Haferlach, Daniel Remondini, Francesco Capozzi, Giovanni Martinelli.

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.

DOI: https://doi.org/10.1038/s41375-021-01318-x
Int J Mol Sci. 2021 Jun 21. pii: 6640. [Epub ahead of print]22(12):

Mitochondrial Function Are Disturbed in the Presence of the Anticancer Drug, 3-Bromopyruvate.

Magdalena Cal, Irwin Matyjaszczyk, Karolina Filik, Rafał Ogórek, Young Ko, Stanisław Ułaszewski.

  3-bromopuryvate (3-BP) is a compound with unique antitumor activity. It has a selective action against tumor cells that exhibit the Warburg effect. It has been proven that the action of 3-BP is pleiotropic: it acts on proteins, glycolytic enzymes, reduces the amount of ATP, induces the formation of ROS (reactive oxygen species), and induces nuclear DNA damage. Mitochondria are important organelles for the proper functioning of the cell. The production of cellular energy (ATP), the proper functioning of the respiratory chain, or participation in the production of amino acids are one of the many functions of mitochondria. Here, for the first time, we show on the yeast model that 3-BP acts in the eukaryotic cell also by influence on mitochondria and that agents inhibiting mitochondrial function can potentially be used in cancer therapy with 3-BP. We show that cells with functional mitochondria are more resistant to 3-BP than rho0 cells. Using an MTT assay (a colorimetric assay for assessing cell metabolic activity), we demonstrated that 3-BP decreased mitochondrial activity in yeast in a dose-dependent manner. 3-BP induces mitochondrial-dependent ROS generation which results in ∆sod2, ∆por1, or ∆gpx1 mutant sensitivity to 3-BP. Probably due to ROS mtDNA lesions rise during 3-BP treatment. Our findings may have a significant impact on the therapy with 3-BP.

Keywords:  3-bromopyruvate; mitochondria; mtDNA damage; oxidative stress; superoxide generation; yeast

DOI:  https://doi.org/10.3390/ijms22126640
Nat Cancer. 2021 Apr;2(4): 414-428

FATTY ACID SYNTHESIS IS REQUIRED FOR BREAST CANCER BRAIN METASTASIS.

Gino B Ferraro, Ahmed Ali, Alba Luengo, David P Kodack, Amy Deik, Keene L Abbott, Divya Bezwada, Landry Blanc, Brendan Prideaux, Xin Jin, Jessica M Possada, Jiang Chen, Christopher R Chin, Zohreh Amoozgar, Raphael Ferreira, Ivy Chen, Kamila Naxerova, Christopher Ng, Anna M Westermark, Mark Duquette, Sylvie Roberge, Neal I Lindeman, Costas A Lyssiotis, Jens Nielsen, David E Housman, Dan G Duda, Elena Brachtel, Todd R Golub, Lewis C Cantley, John M Asara, Shawn M Davidson, Dai Fukumura, Véronique A Dartois, Clary B Clish, Rakesh K Jain, Matthew G Vander Heiden.

Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in brain. We determine that this phenotype is an adaptation to decreased lipid availability in brain relative to other tissues, resulting in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

DOI: https://doi.org/10.1038/s43018-021-00183-y
Int J Mol Sci. 2021 Jun 15. pii: 6384. [Epub ahead of print]22(12):

Responsiveness to Hedgehog Pathway Inhibitors in T-Cell Acute Lymphoblastic Leukemia Cells Is Highly Dependent on 5'AMP-Activated Kinase Inactivation.

Valeria Tosello, Deborah Bongiovanni, Ludovica Di Martino, Cinzia Franchin, Paola Zanovello, Giorgio Arrigoni, Erich Piovan.

  Numerous studies have shown that hedgehog inhibitors (iHHs) only partially block the growth of tumor cells, especially in vivo. Leukemia often expands in a nutrient-depleted environment (bone marrow and thymus). In order to identify putative signaling pathways implicated in the adaptive response to metabolically adverse conditions, we executed quantitative phospho-proteomics in T-cell acute lymphoblastic leukemia (T-ALL) cells subjected to nutrient-depleted conditions (serum starvation). We found important modulations of peptides phosphorylated by critical signaling pathways including casein kinase, mammalian target of rapamycin, and 5'AMP-activated kinase (AMPK). Surprisingly, in T-ALL cells, AMPK signaling was the most consistently downregulated pathway under serum-depleted conditions, and this coincided with increased GLI1 expression and sensitivity to iHHs, especially the GLI1/2 inhibitor GANT-61. Increased sensitivity to GANT-61 was also found following genetic inactivation of the catalytic subunit of AMPK (AMPKα1) or pharmacological inhibition of AMPK by Compound C. Additionally, patient-derived xenografts showing high GLI1 expression lacked activated AMPK, suggesting an important role for this signaling pathway in regulating GLI1 protein levels. Further, joint targeting of HH and AMPK signaling pathways in T-ALL cells by GANT-61 and Compound C significantly increased the therapeutic response. Our results suggest that metabolic adaptation that occurs under nutrient starvation in T-ALL cells increases responsiveness to HH pathway inhibitors through an AMPK-dependent mechanism and that joint therapeutic targeting of AMPK signaling and HH signaling could represent a valid therapeutic strategy in rapidly expanding tumors where nutrient availability becomes limiting.

Keywords:  5′AMP-activated kinase signaling; T-cell lymphoblastic leukemia; hedgehog signaling; leukemia growth; targeted therapy

DOI:  https://doi.org/10.3390/ijms22126384
Cancers (Basel). 2021 Jun 25. pii: 3191. [Epub ahead of print]13(13):

Hampering Stromal Cells in the Tumor Microenvironment as a Therapeutic Strategy to Destem Cancer Stem Cells.

Katherine Po Sin Chung, Rainbow Wing Hei Leung, Terence Kin Wah Lee.

  Cancer stem cells (CSCs) within the tumor bulk play crucial roles in tumor initiation, recurrence and therapeutic resistance. In addition to intrinsic regulation, a growing body of evidence suggests that the phenotypes of CSCs are also regulated extrinsically by stromal cells in the tumor microenvironment (TME). Here, we discuss the current knowledge of the interplay between stromal cells and cancer cells with a special focus on how stromal cells drive the stemness of cancer cells and immune evasive mechanisms of CSCs. Knowledge gained from the interaction between CSCs and stromal cells will provide a mechanistic basis for the development of novel therapeutic strategies for the treatment of cancers.

Keywords:  cancer; cancer stem cells; immune cells; stromal cells; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers13133191