bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–06–27
nine papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia.
  2. The Role of the Renin-Angiotensin System in the Cancer Stem Cell Niche.
  3. Adrenomedullin Expression Characterizes Leukemia Stem Cells and Associates With an Inflammatory Signature in Acute Myeloid Leukemia.
  4. Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.
  5. Protein tyrosine phosphatome metabolic screen identifies TC-PTP as a positive regulator of cancer cell bioenergetics and mitochondrial dynamics.
  6. Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia.
  7. Effective killing of acute myeloid leukemia by TIM-3 targeted chimeric antigen receptor T cells.
  8. The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance.
  9. TIM-3 in normal and malignant hematopoiesis: structure, function and signaling pathways.
  1. iScience. 2021 Jun 25. 24(6): 102651
    Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia.
    Barry M Zee, Kamrine E Poels, Cong-Hui Yao, Kimihito C Kawabata, Gongwei Wu, Cihangir Duy, William D Jacobus, Elizabeth Senior, Jennifer E Endress, Ashwini Jambhekar, Scott B Lovitch, Jiexian Ma, Abhinav Dhall, Isaac S Harris, M Andres Blanco, David B Sykes, Jonathan D Licht, David M Weinstock, Ari Melnick, Marcia C Haigis, Franziska Michor, Yang Shi.
      A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML. To identify metabolic targets that interact with LSD1 inhibition to promote myeloid maturation, we screened a small molecule library to identify druggable substrates. We found that differentiation caused by LSD1 inhibition is enhanced by combined perturbation of purine nucleotide salvage and de novo lipogenesis pathways, and identified multiple lines of evidence to support the specificity of these pathways and suggest a potential basis of how perturbation of these pathways may interact synergistically to promote myeloid differentiation. In sum, these findings suggest potential drug combination strategies in the treatment of AML.
    Keywords:  molecular biology; stem cell research; systems biology
    DOI:  https://doi.org/10.1016/j.isci.2021.102651
  2. J Histochem Cytochem. 2021 Jun 24. 221554211026295
    The Role of the Renin-Angiotensin System in the Cancer Stem Cell Niche.
    Ethan J Kilmister, Swee T Tan.
      Cancer stem cells (CSCs) drive metastasis, treatment resistance, and tumor recurrence. CSCs reside within a niche, an anatomically distinct site within the tumor microenvironment (TME) that consists of malignant and non-malignant cells, including immune cells. The renin-angiotensin system (RAS), a critical regulator of stem cells and key developmental processes, plays a vital role in the TME. Non-malignant cells within the CSC niche and stem cell signaling pathways such as the Wnt, Hedgehog, and Notch pathways influence CSCs. Components of the RAS and cathepsins B and D that constitute bypass loops of the RAS are expressed on CSCs in many cancer types. There is extensive in vitro and in vivo evidence showing that RAS inhibition reduces tumor growth, cell proliferation, invasion, and metastasis. However, there is inconsistent epidemiological data on the effect of RAS inhibitors on cancer incidence and survival outcomes, attributed to different patient characteristics and methodologies used between studies. Further mechanistic studies are warranted to investigate the precise effects of the RAS on CSCs directly and/or the CSC niche. Targeting the RAS, its bypass loops, and convergent signaling pathways participating in the TME and other key stem cell pathways that regulate CSCs may be a novel approach to cancer treatment.
    Keywords:  angiogenesis; cancer; cancer stem cell; cancer stem cell niche; drug repurposing; drug resistance; microenvironmental niche; renin–angiotensin system; stemness; tumor heterogeneity; tumor immune infiltrate; tumor microenvironment
    DOI:  https://doi.org/10.1369/00221554211026295
  3. Front Oncol. 2021 ;11 684396
    Adrenomedullin Expression Characterizes Leukemia Stem Cells and Associates With an Inflammatory Signature in Acute Myeloid Leukemia.
    Giorgia Simonetti, Davide Angeli, Elisabetta Petracci, Eugenio Fonzi, Susanna Vedovato, Alessandra Sperotto, Antonella Padella, Martina Ghetti, Anna Ferrari, Valentina Robustelli, Rosa Di Liddo, Maria Teresa Conconi, Cristina Papayannidis, Claudio Cerchione, Michela Rondoni, Annalisa Astolfi, Emanuela Ottaviani, Giovanni Martinelli, Michele Gottardi.
      Adrenomedullin (ADM) is a hypotensive and vasodilator peptide belonging to the calcitonin gene-related peptide family. It is secreted in vitro by endothelial cells and vascular smooth muscle cells, and is significantly upregulated by a number of stimuli. Moreover, ADM participates in the regulation of hematopoietic compartment, solid tumors and leukemias, such as acute myeloid leukemia (AML). To better characterize ADM involvement in AML pathogenesis, we investigated its expression during human hematopoiesis and in leukemic subsets, based on a morphological, cytogenetic and molecular characterization and in T cells from AML patients. In hematopoietic stem/progenitor cells and T lymphocytes from healthy subjects, ADM transcript was barely detectable. It was expressed at low levels by megakaryocytes and erythroblasts, while higher levels were measured in neutrophils, monocytes and plasma cells. Moreover, cells populating the hematopoietic niche, including mesenchymal stem cells, showed to express ADM. ADM was overexpressed in AML cells versus normal CD34+ cells and in the subset of leukemia compared with hematopoietic stem cells. In parallel, we detected a significant variation of ADM expression among cytogenetic subgroups, measuring the highest levels in inv(16)/t(16;16) or complex karyotype AML. According to the mutational status of AML-related genes, the analysis showed a lower expression of ADM in FLT3-ITD, NPM1-mutated AML and FLT3-ITD/NPM1-mutated cases compared with wild-type ones. Moreover, ADM expression had a negative impact on overall survival within the favorable risk class, while showing a potential positive impact within the subgroup receiving a not-intensive treatment. The expression of 135 genes involved in leukemogenesis, regulation of cell proliferation, ferroptosis, protection from apoptosis, HIF-1α signaling, JAK-STAT pathway, immune and inflammatory responses was correlated with ADM levels in the bone marrow cells of at least two AML cohorts. Moreover, ADM was upregulated in CD4+ T and CD8+ T cells from AML patients compared with healthy controls and some ADM co-expressed genes participate in a signature of immune tolerance that characterizes CD4+ T cells from leukemic patients. Overall, our study shows that ADM expression in AML associates with a stem cell phenotype, inflammatory signatures and genes related to immunosuppression, all factors that contribute to therapy resistance and disease relapse.
    Keywords:  acute myeloid leukemia; adrenomedullin; hematopoiesis; inflammation; leukemia stem cells
    DOI:  https://doi.org/10.3389/fonc.2021.684396
  4. Cell Death Dis. 2021 Jun 19. 12(7): 634
    Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.
    Liang Zhang, Jianong Zhang, Yan Liu, Pingzhao Zhang, Ji Nie, Rui Zhao, Qin Shi, Huiru Sun, Dongyue Jiao, Yingji Chen, Xiaying Zhao, Yan Huang, Yao Li, Jian-Yuan Zhao, Wei Xu, Shi-Min Zhao, Chenji Wang.
      Signal transducer and activator 5a (STAT5A) is a classical transcription factor that plays pivotal roles in various biological processes, including tumor initiation and progression. A fraction of STAT5A is localized in the mitochondria, but the biological functions of mitochondrial STAT5A remain obscure. Here, we show that STAT5A interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme connecting two key metabolic pathways, glycolysis and the tricarboxylic acid cycle. Mitochondrial STAT5A disrupts PDC integrity, thereby inhibiting PDC activity and remodeling cellular glycolysis and oxidative phosphorylation. Mitochondrial translocation of STAT5A is increased under hypoxic conditions. This strengthens the Warburg effect in cancer cells and promotes in vitro cell growth under hypoxia and in vivo tumor growth. Our findings indicate distinct pro-oncogenic roles of STAT5A in energy metabolism, which is different from its classical function as a transcription factor.
    DOI:  https://doi.org/10.1038/s41419-021-03908-0
  5. FASEB J. 2021 Jul;35(7): e21708
    Protein tyrosine phosphatome metabolic screen identifies TC-PTP as a positive regulator of cancer cell bioenergetics and mitochondrial dynamics.
    Valerie Vinette, Isabelle Aubry, Hayley Insull, Noriko Uetani, Serge Hardy, Michel L Tremblay.
      Metabolic reprogramming occurs in cancer cells and is regulated partly by the opposing actions of tyrosine kinases and tyrosine phosphatases. Several members of the protein tyrosine phosphatase (PTP) superfamily have been linked to cancer as either pro-oncogenic or tumor-suppressive enzymes. In order to investigate which PTPs can modulate the metabolic state of cancer cells, we performed an shRNA screen of PTPs in HCT116 human colorectal cancer cells. Among the 72 PTPs efficiently targeted, 24 were found to regulate mitochondrial respiration, 8 as negative and 16 as positive regulators. Of the latter, we selected TC-PTP (PTPN2) for further characterization since inhibition of this PTP resulted in major functional defects in oxidative metabolism without affecting glycolytic flux. Transmission electron microscopy revealed an increase in the number of damaged mitochondria in TC-PTP-null cells, demonstrating the potential role of this PTP in regulating mitochondrial homeostasis. Downregulation of STAT3 by siRNA-mediated silencing partially rescued the mitochondrial respiration defect observed in TC-PTP-deficient cells, supporting the role of this signaling axis in regulating mitochondrial activity. In addition, mitochondrial stress prevented an increased expression of electron transport chain-related genes in cells with TC-PTP silencing, correlating with decreased ATP production, cellular proliferation, and migration. Our shRNA-based metabolic screen revealed that PTPs can serve as either positive or negative regulators of cancer cell metabolism. Taken together, our findings uncover a new role for TC-PTP as an activator of mitochondrial metabolism, validating this PTP as a key target for cancer therapeutics.
    Keywords:  PTPN2; TC-PTP; cancer; metabolism; mitochondria; protein tyrosine phosphatases
    DOI:  https://doi.org/10.1096/fj.202100207R
  6. Nat Cancer. 2021 Mar;2(3): 284-299
    Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia.
    Yoshihiro Gocho, Jingjing Liu, Jianzhong Hu, Wentao Yang, Neekesh V Dharia, Jingliao Zhang, Hao Shi, Guoqing Du, August John, Ting-Nien Lin, Jeremy Hunt, Xin Huang, Lauren Rowland, Lei Shi, Dylan Maxwell, Brandon Smart, Kristine Crews, Wenjian Yang, Kohei Hagiwara, Yingchi Zhang, Kathryn Roberts, Hong Wang, Elias Jabbour, Wendy Stock, Bartholomew Eisfelder, Elisabeth Paietta, Scott Newman, Giovanni Roti, Mark Litzow, Jinghui Zhang, Junmin Peng, Hongbo Chi, Stanley Pounds, Mary V Relling, Hiroto Inaba, Xiaofan Zhu, Steven Kornblau, Ching-Hon Pui, Marina Konopleva, David Teachey, Charles G Mullighan, Kimberly Stegmaier, William E Evans, Jiyang Yu, Jun J Yang.
      T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia' drug sensitivities ex vivo, we discovered that 44.4% of childhood and 16.7% of adult T-ALL cases exquisitely respond to dasatinib. Applying network-based systems pharmacology analyses to examine signal circuitry, we identified preTCR-LCK activation as the driver of dasatinib sensitivity, and T-ALL-specific LCK dependency was confirmed in genome-wide CRISPR-Cas9 screens. Dasatinib-sensitive T-ALLs exhibited high BCL-XL and low BCL2 activity and venetoclax resistance. Discordant sensitivity of T-ALL to dasatinib and venetoclax is strongly correlated with T-cell differentiation, particularly with the dynamic shift in LCK vs. BCL2 activation. Finally, single-cell analysis identified leukemia heterogeneity in LCK and BCL2 signaling and T-cell maturation stage, consistent with dasatinib response. In conclusion, our results indicate that developmental arrest in T-ALL drives differential activation of preTCR-LCK and BCL2 signaling in this leukemia, providing unique opportunities for targeted therapy.
    DOI:  https://doi.org/10.1038/s43018-020-00167-4
  7. Mol Cancer Ther. 2021 Jun 22. pii: molcanther.0155.2020. [Epub ahead of print]
    Effective killing of acute myeloid leukemia by TIM-3 targeted chimeric antigen receptor T cells.
    Wen-Hsin Sandy Lee, Zhiyong Ye, Alice M S Cheung, Y P Sharon Goh, Hsueh Ling Janice Oh, Ravisankar Rajarethinam, Siok Ping Yeo, Mun Kuen Soh, Esther Hian Li Chan, Lip Kun Tan, Soo-Yong Tan, Charles Chuah, Wee Joo Chng, John E Connolly, Cheng-I Wang.
      Acute myeloid leukemia (AML) is an aggressive disease with poor outcomes, overwhelmingly due to relapse. Minimal Residual disease (MRD), defined as the persistence of leukemic cells after chemotherapy treatment, is thought to be the major cause of relapse. The origins of relapse in AML have been traced to rare therapy-resistant leukemic stem cells (LSCs) that are already present at diagnosis. Effective treatment strategies for long-term remission are lacking, as it has been difficult to eliminate LSCs with conventional therapy. Here we proposed a new approach based on the chimeric antigen receptor (CAR)-directed T lymphocytes, targeting T cell immunoglobulin and mucin domain 3 (TIM-3) to treat MRD in AML patients. TIM-3 is selected as the target because it is highly expressed on AML blasts and LSCs in most subtypes regardless of patient's genetic characteristics and treatment course. Moreover, it is absent in the normal hematopoietic stem cells (HSCs), granulocytes, naïve lymphocytes and most normal non-hematopoietic tissues. Using a naïve human Fab phage display library, we isolated an anti-human TIM-3 antibody and designed a second-generation anti-TIM-3 CAR. Our anti-TIM-3 CAR T cells exhibit potent anti-leukemic activity against AML cell lines and primary AML blasts, and in the mouse models. More importantly, we demonstrate efficient killing of the primary LSCs directly isolated from the patients. Hence, eradication of the LSCs present in the MRD by anti-TIM-3 CAR T cells therapy following the first line treatment may improve the clinical outcomes of AML patients.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0155
  8. Cancer Cell. 2021 Jun 23. pii: S1535-6108(21)00286-5. [Epub ahead of print]
    The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance.
    Sunil K Joshi, Tamilla Nechiporuk, Daniel Bottomly, Paul D Piehowski, Julie A Reisz, Janét Pittsenbarger, Andy Kaempf, Sara J C Gosline, Yi-Ting Wang, Joshua R Hansen, Marina A Gritsenko, Chelsea Hutchinson, Karl K Weitz, Jamie Moon, Francesca Cendali, Thomas L Fillmore, Chia-Feng Tsai, Athena A Schepmoes, Tujin Shi, Osama A Arshad, Jason E McDermott, Ozgun Babur, Kevin Watanabe-Smith, Emek Demir, Angelo D'Alessandro, Tao Liu, Cristina E Tognon, Jeffrey W Tyner, Shannon K McWeeney, Karin D Rodland, Brian J Druker, Elie Traer.
      Our study details the stepwise evolution of gilteritinib resistance in FLT3-mutated acute myeloid leukemia (AML). Early resistance is mediated by the bone marrow microenvironment, which protects residual leukemia cells. Over time, leukemia cells evolve intrinsic mechanisms of resistance, or late resistance. We mechanistically define both early and late resistance by integrating whole-exome sequencing, CRISPR-Cas9, metabolomics, proteomics, and pharmacologic approaches. Early resistant cells undergo metabolic reprogramming, grow more slowly, and are dependent upon Aurora kinase B (AURKB). Late resistant cells are characterized by expansion of pre-existing NRAS mutant subclones and continued metabolic reprogramming. Our model closely mirrors the timing and mutations of AML patients treated with gilteritinib. Pharmacological inhibition of AURKB resensitizes both early resistant cell cultures and primary leukemia cells from gilteritinib-treated AML patients. These findings support a combinatorial strategy to target early resistant AML cells with AURKB inhibitors and gilteritinib before the expansion of pre-existing resistance mutations occurs.
    Keywords:  AML; Aurora kinase B; FLT3; NRAS; drug resistance; gilteritinib; lipid metabolism; quizartinib; tumor microenvironment; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1016/j.ccell.2021.06.003
  9. Cancer Sci. 2021 Jun 22.
    TIM-3 in normal and malignant hematopoiesis: structure, function and signaling pathways.
    Yoshikane Kikushige.
      Acute myeloid leukemia (AML) is hierarchically organized by self-renewing leukemic stem cells (LSCs). LSCs originate from hematopoietic stem cells (HSCs) by acquiring multistep leukemogenic events. To specifically eradicate LSCs, while keeping normal HSCs intact, the discrimination of LSCs from HSCs is important. We have identified T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as an LSC-specific surface molecule in human myeloid malignancies, and demonstrated its essential function in maintaining the self-renewal ability of LSCs. TIM-3 has been intensively investigated as a "co-inhibitory" or "immune checkpoint" molecule of T cells. However, little is known about its distinct function in T cells and myeloid malignancies. In this review, we discuss the structure of TIM-3, its function in normal blood cells and LSCs, emphasizing the specific signaling pathways involved, as well as the therapeutic applications of TIM-3 molecules in human myeloid malignancies.
    Keywords:  T-cell immunity; TIM-3; acute myeloid leukemia; and immune checkpoint inhibitor; leukemic stem cells
    DOI:  https://doi.org/10.1111/cas.15042
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