bims-almceb 2021-02-07 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–02–07
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy.
Protein Kinase C-β-dependent changes in the glucose metabolism of bone marrow stromal cells of chronic lymphocytic leukemia.
Lymphocyte doubling time in chronic lymphocytic leukemia modern era: a real-life study in 848 unselected patients.
The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer.
Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia.
A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients. Final results of the GIMEMA LAL1509 protocol.
Dysregulation of mitophagy and mitochondrial homeostasis in cancer stem cells: Novel mechanism for anti-CSCs Targeted Cancer Therapy.
ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer.

Cell Immunol. 2021 Jan 19. pii: S0008-8749(21)00005-8. [Epub ahead of print]362 104286

Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy.

Adeleye Oluwatosin Adeshakin, Wan Liu, Funmilayo O Adeshakin, Lukman O Afolabi, Mengqi Zhang, Guizhong Zhang, Lulu Wang, Zhihuan Li, Lilong Lin, Qin Cao, Dehong Yan, Xiaochun Wan.

  Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy against the PD-1/PD-L1 axis, it induces sustained responses in a sizeable minority of cancer patients due to the activation of immunosuppressive factors such as myeloid-derived suppressor cells (MDSCs). Inhibiting the immunosuppressive function of MDSCs is critical for successful cancer ICB therapy. Interestingly, lipid metabolism is a crucial factor in modulating MDSCs function. Fatty acid transport protein 2 (FATP2) conferred the function of PMN-MDSCs in cancer via the upregulation of arachidonic acid metabolism. However, whether regulating lipid accumulation in MDSCs by targeting FATP2 could block MDSCs reactive oxygen species (ROS) production and enhance PD-L1 blockade-mediated tumor immunotherapy remains unexplored. Here we report that FATP2 regulated lipid accumulation, ROS, and immunosuppressive function of MDSCs in tumor-bearing mice. Tumor cells-derived granulocyte macrophage-colony stimulating factor (GM-CSF) induced FATP2 expression in MDSCs by activation of STAT3 signaling pathway. Pharmaceutical blockade of FATP2 expression in MDSCs by lipofermata decreased lipid accumulation, reduced ROS, blocked immunosuppressive activity, and consequently inhibited tumor growth. More importantly, lipofermata inhibition of FATP2 in MDSCs enhanced anti-PD-L1 tumor immunotherapy via the upregulation of CD107a and reduced PD-L1 expression on tumor-infiltrating CD8+T-cells. Furthermore, the combination therapy blocked MDSC's suppressive role on T- cells thereby enhanced T-cell's ability for the production of IFN-γ. These findings indicate that FATP2 plays a key role in modulating lipid accumulation-induced ROS in MDSCs and targeting FATP2 in MDSCs provides a novel therapeutic approach to enhance anti-PD-L1 cancer immunotherapy.

Keywords:  Anti-PD-L1 tumor immunotherapy; FATP2; Lipid metabolism; MDSCs; ROS

DOI:  https://doi.org/10.1016/j.cellimm.2021.104286
Stem Cells. 2021 Feb 04.

Protein Kinase C-β-dependent changes in the glucose metabolism of bone marrow stromal cells of chronic lymphocytic leukemia.

Franziska von Heydebrand, Maximilian Fuchs, Meik Kunz, Simon Voelkl, Anita N Kremer, Robert A J Oostendorp, Jochen Wilke, Michael Leitges, Alexander Egle, Andreas Mackensen, Gloria Lutzny-Geier.

  Survival of chronic lymphocytic leukemia (CLL) cells critically depends on the support of an adapted and therefore appropriate tumor microenvironment (TME). Increasing evidence suggests that B-cell receptor associated kinases such as protein kinase C (PKC)-β or Lyn kinase, are essential for the formation of a microenvironment supporting leukemic growth. Here, we describe the impact of PKCβ on the glucose metabolism in bone marrow stromal cells (BMSC) upon CLL contact. BMSC get activated by CLL contact expressing stromal PKCβ that diminishes mitochondrial stress and apoptosis in CLL cells by stimulating glucose uptake. In BMSC, the upregulation of PKCβ results in increased mitochondrial depolarization and leads to a metabolic switch towards oxidative phosphorylation. Additionally, PKCβ-deficient BMSC regulates the expression of Hnf1 promoting stromal insulin signaling after CLL contact. Our data suggest that targeting PKCβ and the glucose metabolism of the leukemic niche could be a potential therapeutic strategy to overcome stroma-mediated drug-resistance. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: The bystander relationship between cancer cells and BMSC leads to pro-survival activities of BMSC, like the expression of stromal PKCβ, which contributes to cancer growth and progression. Increasing evidence highlights that leukemic cells can modify metabolic pathways of neighboring cells in order to satisfy their energy demands. Therefore, the metabolic characterization of the tumor microenvironment might give us new strategies to target the microenvironment as an alternative to cytotoxic therapies. Here, we can show for the first time a link between stromal metabolism and PKCβ expression in BMSC after contact to primary CLL cells.

Keywords:  BMSC; CLL; PKCβ; glucose metabolism

DOI:  https://doi.org/10.1002/stem.3352
Leukemia. 2021 Feb 04.

Lymphocyte doubling time in chronic lymphocytic leukemia modern era: a real-life study in 848 unselected patients.

Tycho Baumann, Riccardo Moia, Gianluca Gaidano, Julio Delgado, Adalgisa Condoluci, Neus Villamor, Anil Babu Payedimarri, Dolors Costa, Andrea Patriarca, Carlos Jiménez-Vicente, Davide Rossi, Emili Montserrat.

The prognostic significance of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was identified when the biology of the disease was poorly understood and therapy was not effective. We assessed the clinical and biological significance of LDT in 848 CLL patients in a real-life setting and the context of new biomarkers and effective therapy. A short LDT (≤12 months) was enriched for adverse biomarkers. Patients with a rapid LDT did need therapy shortly after diagnosis (median 23 months vs. not reached; p < 0.001) and had a poorer overall survival (median 95 months vs. not reached p < 0.001). LDT, IGHV mutational status, Beta-2 microglobulin, and Rai clinical stage were independent predictors for time to first treatment in the whole series and in Binet stage A patients. No correlation was observed between LDT and response to chemoimmunotherapy. However, a short LDT along with age ≥65 years, high-risk FISH (del(17p), del(11q)), unmutated IGHV, increased Beta-2 microglobulin, and TP53 mutations predicted short survival. Moreover, the prognostic significance of LDT was independent of the CLL-IPI and the Barcelona/Brno prognostic model. LDT remains an important outcome marker in the modern CLL era and should be incorporated into the clinical assessment and stratification of CLL patients.

DOI: https://doi.org/10.1038/s41375-021-01149-w
J Diabetes Metab Disord. 2020 Dec;19(2): 1731-1775

The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer.

Lakshmipathi Vadlakonda, Meera Indracanti, Suresh K Kalangi, B Meher Gayatri, Navya G Naidu, Aramati B M Reddy.

   Purpose: Re-examine the current metabolic models.
Methods: Review of literature and gene networks.
Results: Insulin activates Pi uptake, glutamine metabolism to stabilise lipid membranes. Tissue turnover maintains the metabolic health. Current model of intermediary metabolism (IM) suggests glucose is the source of energy, and anaplerotic entry of fatty acids and amino acids into mitochondria increases the oxidative capacity of the TCA cycle to produce the energy (ATP). The reduced cofactors, NADH and FADH2, have different roles in regulating the oxidation of nutrients, membrane potentials and biosynthesis. Trans-hydrogenation of NADH to NADPH activates the biosynthesis. FADH2 sustains the membrane potential during the cell transformations. Glycolytic enzymes assume the non-canonical moonlighting functions, enter the nucleus to remodel the genetic programmes to affect the tissue turnover for efficient use of nutrients. Glycosylation of the CD98 (4F2HC) stabilises the nutrient transporters and regulates the entry of cysteine, glutamine and BCAA into the cells. A reciprocal relationship between the leucine and glutamine entry into cells regulates the cholesterol and fatty acid synthesis and homeostasis in cells. Insulin promotes the Pi transport from the blood to tissues, activates the mitochondrial respiratory activity, and glutamine metabolism, which activates the synthesis of cholesterol and the de novo fatty acids for reorganising and stabilising the lipid membranes for nutrient transport and signal transduction in response to fluctuations in the microenvironmental cues. Fatty acids provide the lipid metabolites, activate the second messengers and protein kinases. Insulin resistance suppresses the lipid raft formation and the mitotic slippage activates the fibrosis and slow death pathways.

Keywords:  CD98; Fatty acids; Glutamine; Leucine; Mitochondrial pyruvate carrier proteins (MPC1&2); Tissue turnover; mTORC1

DOI:  https://doi.org/10.1007/s40200-020-00566-5
Stem Cells. 2021 Feb 04.

Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia.

Yasuhiro Shingai, Takafumi Yokota, Daisuke Okuzaki, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi, Tomoaki Ueda, Takayuki Ozawa, Ritsuko Nakai, Akira Tanimura, Michiko Ichii, Hirohiko Shibayama, Yuzuru Kanakura, Naoki Hosen.

  Heterogeneity of leukemia stem cells (LSCs) is involved in their collective chemoresistance. To eradicate LSCs, it is necessary to understand the mechanisms underlying their heterogeneity. Here, we aimed to identify signals responsible for heterogeneity and variation of LSCs in human acute myeloid leukemia (AML). Monitoring expression levels of endothelial cell-selective adhesion molecule (ESAM), a hematopoietic stem cell-related marker, was useful to detect the plasticity of AML cells. While healthy human hematopoietic stem/progenitor cells robustly expressed ESAM, AML cells exhibited heterogeneous ESAM expression. Interestingly, ESAM- and ESAM+ leukemia cells obtained from AML patients were mutually interconvertible in culture. KG1a and CMK, human AML clones, also represented the heterogeneity in terms of ESAM expression. Single cell culture with ESAM- or ESAM+ AML clones recapitulated the phenotypic interconversion. The phenotypic alteration was regulated at the gene expression level, and RNA sequencing revealed activation of TGFβ signaling in these cells. AML cells secreted TGFβ1, which autonomously activated TGFβ pathway and induced their phenotypic variation. Surprisingly, TGFβ signaling blockade inhibited not only the variation but also the proliferation of AML cells. Therefore, autonomous activation of TGFβ signaling underlies the LSC heterogeneity, which may be a promising therapeutic target for AML. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: We have shown the autonomous TGFβ signaling as one of the molecular mechanisms underlying heterogeneity and variability of leukemia stem cells associated with human acute myeloid leukemia (AML). By monitoring the ESAM expression, we found that human AML cells were phenotypically heterogeneous and variable. ESAM- and ESAM+ AML cells were mutually convertible in culture. We determined that autocrine TGFβ signaling was involved in AML cell heterogeneity and variability. Inhibiting the TGFβ pathway not only suppressed ESAM variability, but also induced AML cell apoptosis. Thus, mechanisms promoting the heterogeneity and variability of LSCs can be therapeutic targets against intractable AML.

Keywords:  Acute myeloid leukemia; Autonomous signaling; Chemoresistance; Endothelial cell-selective adhesion molecule; Heterogeneity; Leukemia stem cells; Phenotypic variation; TGFβ

DOI:  https://doi.org/10.1002/stem.3348
Haematologica. 2021 Feb 04.

A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients. Final results of the GIMEMA LAL1509 protocol.

Sabina Chiaretti, Michela Ansuinelli, Antonella Vitale, Loredana Elia, Mabel Matarazzo, Alfonso Piciocchi, Paola Fazi, Francesco Di Raimondo, Lidia Santoro, Francesco Fabbiano, Catello Califano, Giovanni Martinelli, Francesca Ronco, Felicetto Ferrara, Nicola Cascavilla, Catia Bigazzi, Alessandra Tedeschi, Simona Sica, Nicola Di Renzo, Angela Melpignano, Germana Beltrami, Marco Vignetti, Robin Foa.

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39.

DOI: https://doi.org/10.3324/haematol.2020.260935
Br J Pharmacol. 2021 Feb 01.

Dysregulation of mitophagy and mitochondrial homeostasis in cancer stem cells: Novel mechanism for anti-CSCs Targeted Cancer Therapy.

Prakash P Praharaj, Birija Sankar Patro, Sujit K Bhutia.

  Despite the potential of cancer medicine, cancer stem cells (CSCs) associated with chemoresistance and disease recurrence are the significant challenges currently opposing the efficacy of available cancer treatment options. Mitochondrial dynamics involving the fission-fusion cycle and mitophagy are the major contributing factor for better adaptation, enabling CSCs to survive and grow better under tumor microenvironment associated stress. Moreover, mitophagy is balanced with mitochondrial biogenesis to maintain mitochondrial homeostasis in CSCs, which are necessary for the growth and maintenance of CSCs and regulate metabolic switching from glycolysis to oxidative phosphorylation in the CSCs. Therefore, in this review, we discussed different aspects of mitochondrial dynamics, mitophagy, and mitochondrial homeostasis and their impact on modulating CSCs behavior during cancer development. Moreover, the efficacy of pharmacological targeting of these cellular processes using antiCSC drugs in combination with currently available chemotherapeutic drugs improves the patient's survival of aggressive cancer types.

Keywords:  Biogenesis; Cancer stem cells; Mitochondrial fission; Mitochondrial fusion; Mitochondrial retrograde response; Oxidative phosphorylation; Targeted cancer therapy

DOI:  https://doi.org/10.1111/bph.15401
Cancer Res. 2021 Feb 05. pii: canres.2511.2020. [Epub ahead of print]

ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer.

Margaret M Centenera, Julia S Scott, Jelle Machiels, Zeyad D Nassar, Deanna C Miller, Irene Zininos, Jonas Dehairs, Ingrid J G Burvenich, Giorgia Zadra, Paolo Chetta, Clyde Bango, Emma Evergren, Natalie K Ryan, Joanna L Gillis, Chui Yan Mah, Terence Tieu, Adrienne R Hanson, Ryan Carelli, Katarzyna Bloch, Vasilios Panagopoulos, Etienne Waelkens, Rita Derua, Elizabeth D Williams, Andreas Evdokioou, Anna Cifuentes-Rius, Nicolas H Voelcker, Ian G Mills, Wayne D Tilley, Andrew M Scott, Massimo Loda, Luke A Selth, Johannes V Swinnen, Lisa M Butler.

The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR-dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remain undefined. Using mass spectrometry-based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale datasets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared to non-malignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a pro-tumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-2511