bims-almceb 2022-02-13 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–02–13
nine papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Metformin sensitizes AML cells to chemotherapy through blocking mitochondrial transfer from stromal cells to AML cells.
A mechanistic modeling framework reveals the key principles underlying tumor metabolism.
A novel CD34-specific T-cell engager efficiently depletes acute myeloid leukemia and leukemic stem cells in vitro and in vivo.
Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis.
Guanosine primes acute myeloid leukemia for differentiation via guanine nucleotide salvage synthesis.
Targeting OXPHOS and the electronic transport chain in cancer; molecular and therapeutic implications.
SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells.
Time to blur the blast boundaries.
Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy.

Cancer Lett. 2022 Feb 02. pii: S0304-3835(22)00051-9. [Epub ahead of print]532 215582

Metformin sensitizes AML cells to chemotherapy through blocking mitochondrial transfer from stromal cells to AML cells.

Ruolan You, Bin Wang, Ping Chen, Xiaoming Zheng, Diyu Hou, Xiaoting Wang, Beiying Zhang, Ling Chen, Dongliang Li, Xinjian Lin, Huifang Huang.

  Interaction between stromal cells and acute myeloid leukemia (AML) cells in bone marrow (BM) is known to contribute importantly to chemoresistance and disease recurrence. Therefore, disruption of a crosstalk between AML cells and BM microenvironment may offer a promising therapeutic strategy for AML treatment. Here, we demonstrate that in a niche-like co-culture system, AML cells took up functional mitochondria from bone marrow stromal cells (BMSCs) and inhibition of such mitochondrial transfer by metformin, the most commonly prescribed drug for type 2 diabetes mellitus, significantly enhanced the chemosensitivity of AML cells co-cultured with BMSCs. The chemo-sensitizing effect of metformin was acted through reducing the mitochondrial transfer and mitochondrial oxidative phosphorylation (OXPHOS) in the recipient AML cells. In addition, metformin potentiated the antitumor efficacy of cytarabine (Ara-C) in vivo in an NCG immunodeficient mouse xenograft model by inhibiting the mitochondrial transfer and OXPHOS activity in the engrafted human AML cells. Altogether, this study identifies a potential application of metformin in sensitizing AML cells to chemotherapy and unveils a novel mechanism by which metformin executes such effect via blocking the mitochondrial transfer from stromal cells to AML cells.

Keywords:  Chemo-sensitizing effect; Chemotherapy resistance; Metformin; Mitochondrial transfer

DOI:  https://doi.org/10.1016/j.canlet.2022.215582
PLoS Comput Biol. 2022 Feb 11. 18(2): e1009841

A mechanistic modeling framework reveals the key principles underlying tumor metabolism.

Shubham Tripathi, Jun Hyoung Park, Shivanand Pudakalakatti, Pratip K Bhattacharya, Benny Abraham Kaipparettu, Herbert Levine.

While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the nutrients and the metabolic pathways they are dependent on. Moreover, tumor cells can switch between different metabolic phenotypes in response to environmental cues and therapeutic interventions. A framework to analyze the observed metabolic heterogeneity and plasticity is, however, lacking. Using a mechanistic model that includes the key metabolic pathways active in tumor cells, we show that the inhibition of phosphofructokinase by excess ATP in the cytoplasm can drive a preference for aerobic glycolysis in fast-proliferating tumor cells. The differing rates of ATP utilization by tumor cells can therefore drive heterogeneity with respect to the presentation of the Warburg effect. Building upon this idea, we couple the metabolic phenotype of tumor cells to their migratory phenotype, and show that our model predictions are in agreement with previous experiments. Next, we report that the reliance of proliferating cells on different anaplerotic pathways depends on the relative availability of glucose and glutamine, and can further drive metabolic heterogeneity. Finally, using treatment of melanoma cells with a BRAF inhibitor as an example, we show that our model can be used to predict the metabolic and gene expression changes in cancer cells in response to drug treatment. By making predictions that are far more generalizable and interpretable as compared to previous tumor metabolism modeling approaches, our framework identifies key principles that govern tumor cell metabolism, and the reported heterogeneity and plasticity. These principles could be key to targeting the metabolic vulnerabilities of cancer.

DOI: https://doi.org/10.1371/journal.pcbi.1009841
Haematologica. 2022 Feb 10.

A novel CD34-specific T-cell engager efficiently depletes acute myeloid leukemia and leukemic stem cells in vitro and in vivo.

Lucas C M Arruda, Arwen Stikvoort, Melanie Lambert, Liqing Jin, Laura Sanchez Rivera, Renato M P Alves, Tales Rocha De Moura, Carsten Mim, Sören Lehmann, Rebecca Axelsson-Robertson, John E Dick, Jonas Mattsson, Björn Önfelt, Mattias Carlsten, Michael Uhlin.

Less than a third of acute myeloid leukemia (AML) patients are cured by chemotherapy and/or hematopoietic stem cell transplantation (HSCT), highlighting the need to develop more efficient drugs. The low efficacy of standard treatments is associated with inadequate depletion of CD34+ blasts and leukemic stem cells (LSCs), the latter a drug-resistant subpopulation of leukemia cells characterized by the CD34+CD38- phenotype. To better target these drug-resistant primitive leukemic cells, we have designed a CD34/CD3 bispecific T-cell engager (BiTE) and characterized its anti-leukemia potential in vitro, ex vivo and in vivo. Our results show that this CD34-specific BiTE induces CD34-dependent T-cell activation and subsequent leukemia cell killing in a dose-dependent manner, further corroborated by enhanced T-cell-mediated killing at the single-cell level. Additionally, the BiTE triggered efficient T-cell-mediated depletion of CD34+ HSCs from peripheral blood stem cell grafts and CD34+ blasts from AML patients. Using a humanized AML xenograft model, we confirmed that the CD34-specific BiTE had in vivo efficacy by depleting CD34+ blasts and LSCs without side effects. Taken together, these data demonstrate robust antitumor effects of the CD34-specific BiTE supporting development of a novel treatment modality with the aim of improving outcomes of patients with AML and myelodysplastic syndromes.

DOI: https://doi.org/10.3324/haematol.2021.279486
Biochem Pharmacol. 2022 Feb 04. pii: S0006-2952(22)00037-5. [Epub ahead of print] 114943

Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis.

Shagun Sharma, Navneet Agnihotri, Sandeep Kumar.

  Advances in cell metabolism over the past few decades have demonstrated glutamine as an essential nutrient for cancer cell survival and proliferation. Glutamine offers a remarkable capacity to fuel diverse metabolic pathways in cancer cells including the Krebs cycle, maintenance of redox homeostasis, and synthesis of cellular building blocks such as nucleic acids, fatty acids, glutathione, and other amino acids. The increase in glutaminolysis has further been linked to the accumulation of oncometabolites such as 2HG (2-Hydroxyglutarate), succinate, fumarate, etc., thereby contributing to tumorigenesis via regulating epigenetic modification of imprinted genes. Therefore, therapeutic targeting of glutaminolysis in cancer cells is worth exploring for possible treatment strategies for cancer management. In this review, we have discussed the detailed mechanism of glutamine uptake, transport, and its instrumental role in rewiring the metabolic adaptation of cancer cells in the tumor microenvironment under nutrient deprivation and hypoxia. Furthermore, we have attempted to provide an updated therapeutic intervention of glutamine metabolism as a treatment strategy for cancer management.

Keywords:  Cancer Cell Metabolism; Glutamine; Glutaminolysis; Tumor Microenvironment, Chemotherapy

DOI:  https://doi.org/10.1016/j.bcp.2022.114943
Am J Cancer Res. 2022 ;12(1): 427-444

Guanosine primes acute myeloid leukemia for differentiation via guanine nucleotide salvage synthesis.

Hanying Wang, Xin He, Zheng Li, Hongchuan Jin, Xian Wang, Ling Li.

Differentiation arrest represents a distinct hallmark of acute myeloid leukemia (AML). Identification of differentiation-induction agents that are effective across various subtypes remains an unmet challenge. GTP biosynthesis is elevated in several types of cancers, considered to support uncontrolled tumor growth. Here we report that GTP overload by supplementation of guanosine, the nucleoside precursor of GTP, poises AML cells for differentiation and growth inhibition. Transcriptome profiling of guanosine-treated AML cells reveals a myeloid differentiation pattern. Importantly, the treatment compromises leukemia progression in AML xenograft models. Mechanistically, GTP overproduction requires sequential metabolic conversions executed by the purine salvage biosynthesis pathway including the involvement of purine nucleoside phosphorylase (PNP) and hypoxanthine phosphoribosyltransferase 1 (HPRT1). Taken together, our study offers novel metabolic insights tethering GTP homeostasis to myeloid differentiation and provides an experimental basis for further clinical investigations of guanosine or guanine nucleotides in the treatment of AML patients.

Keywords: Acute myeloid leukemia; HPRT1; PNP; guanosine 5’-triphosphate; myeloid differentiation
Semin Cancer Biol. 2022 Feb 02. pii: S1044-579X(22)00023-2. [Epub ahead of print]

Targeting OXPHOS and the electronic transport chain in cancer; molecular and therapeutic implications.

John Greene, Ashvina Segaran, Simon Lord.

  Oxidative phosphorylation (OXPHOS) takes place in mitochondria and is the process whereby cells use carbon fuels and oxygen to generate ATP. Formerly OXPHOS was thought to be reduced in tumours and that glycolysis was the critical pathway for generation of ATP but it is now clear that OXPHOS, at least in many tumour types, plays a critical role in delivering the bioenergetic and macromolecular anabolic requirements of cancer cells. There is now great interest in targeting the OXPHOS and the electron transport chain for cancer therapy and in this review article we describe current therapeutic approaches and challenges.

Keywords:  OXPHOS; cancer drugs; cancer metabolism; complex I; electron transport chain

DOI:  https://doi.org/10.1016/j.semcancer.2022.02.002
J Clin Invest. 2022 Feb 10. pii: e155224. [Epub ahead of print]

SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells.

Zhongqiu Wu, Haiyan Huang, Qiaoqiao Han, Zhilin Hu, Xiao-Lu Teng, Rui Ding, Youqiong Ye, Xiaoyan Yu, Ren Zhao, Zhengting Wang, Qiang Zou.

  The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell-derived reactive oxygen species (ROS) triggered cytosolic SENP7-mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell-intrinsic ROS restricted SENP7 cytosolic translocation and repressed CD8+ T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains CD8+ T cell metabolic fitness and effector functions and unveil an oxidative stress-sensing machinery in tumor-infiltrating CD8+ T cells.

Keywords:  Adaptive immunity; Cancer immunotherapy; Immunology; Metabolism; T cells

DOI:  https://doi.org/10.1172/JCI155224
Cancer. 2022 Feb 08.

Time to blur the blast boundaries.

Courtney D DiNardo, Guillermo Garcia-Manero, Hagop M Kantarjian.



Keywords:  AML; MDS; acute myeloid leukemia; blast percentage; classification

DOI:  https://doi.org/10.1002/cncr.34119
Cancer Res. 2022 Feb 11. pii: canres.1168.2021. [Epub ahead of print]

Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy.

Mario R Fernandez, Franz X Schaub, Chunying Yang, Weimin Li, Seongseok Yun, Stephanie K Schaub, Frank C Dorsey, Min Liu, Meredith A Steeves, Andrea Ballabio, Alexandar Tzankov, Zhihua Chen, John M Koomen, Anders E Berglund, John L Cleveland.

MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA transport. Reactivation of the autophagy-lysosomal pathway by TFEB disabled the malignant state by disrupting mitochondrial functions, proteasome activity, amino acid transport, and amino acid and nucleotide metabolism, leading to metabolic anergy, growth arrest and apoptosis. This phenotype provides therapeutic opportunities to disable MYC-driven malignancies, including AA restriction and treatment with proteasome inhibitors.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-1168