bims-almceb 2021-11-14 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–11–14
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison.
Metabolism in tumor microenvironment: Implications for cancer immunotherapy.
Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?
Oncogene-Induced Reprogramming in Acute Lymphoblastic Leukemia: Towards Targeted Therapy of Leukemia-Initiating Cells.
Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy.
The role of mitochondria in cellular senescence.
Cotargeting of Bcl-2 and Mcl-1 Shows Promising Antileukemic Activity against AML Cells Including those with Acquired Cytarabine Resistance.
Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.

Cancers (Basel). 2021 Oct 31. pii: 5484. [Epub ahead of print]13(21):

Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison.

Serena Castelli, Pamela De Falco, Fabio Ciccarone, Enrico Desideri, Maria Rosa Ciriolo.

  Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.

Keywords:  fatty acid oxidation; lipid catabolism; mitochondrial metabolism; reactive oxygen species

DOI:  https://doi.org/10.3390/cancers13215484
MedComm (Beijing). 2020 Jun;1(1): 47-68

Metabolism in tumor microenvironment: Implications for cancer immunotherapy.

Rongchen Shi, Yi-Quan Tang, Hongming Miao.

  Tumor microenvironment is a special environment for tumor survival, which is characterized by hypoxia, acidity, nutrient deficiency, and immunosuppression. The environment consists of the vasculature, immune cells, extracellular matrix, and proteins or metabolic molecules. A large number of recent studies have shown that not only tumor cells but also the immune cells in the tumor microenvironment have undergone metabolic reprogramming, which is closely related to tumor drug resistance and malignant progression. Tumor immunotherapy based on T cells gives patients new hope, but faces the dilemma of low response rate. New strategies sensitizing cancer immunotherapy are urgently needed. Metabolic reprogramming can directly affect the biological activity of tumor cells and also regulate the differentiation and activation of immune cells. The authors aim to review the characteristics of tumor microenvironment, the metabolic changes of tumor-associated immune cells, and the regulatory role of metabolic reprogramming in cancer immunotherapy.

Keywords:  cancer therapy; immunity; metabolism; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.6
Cancers (Basel). 2021 Oct 22. pii: 5319. [Epub ahead of print]13(21):

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

Marilena Ciciarello, Giulia Corradi, Dorian Forte, Michele Cavo, Antonio Curti.

  Acute myeloid leukemia (AML) has been considered for a long time exclusively driven by critical mutations in hematopoietic stem cells. Recently, the contribution of further players, such as stromal and immune bone marrow (BM) microenvironment components, to AML onset and progression has been pointed out. In particular, mesenchymal stromal cells (MSCs) steadily remodel the leukemic niche, not only favoring leukemic cell growth and development but also tuning their responsiveness to treatments. The list of mechanisms driven by MSCs to promote a leukemia drug-resistant phenotype has progressively expanded. Moreover, the relative proportion and the activation status of immune cells in the BM leukemic microenvironment may vary by influencing their reactivity against leukemic cells. In that, the capacity of the stroma to re-program immune cells, thus promoting and/or hampering therapeutic efficacy, is emerging as a crucial aspect in AML biology, adding an extra layer of complexity. Current treatments for AML have mainly focused on eradicating leukemia cells, with little consideration for the leukemia-damaged BM niche. Increasing evidence on the contribution of stromal and immune cells in response to therapy underscores the need to hold the mutual interplay, which takes place in the BM. A careful dissection of these interactions will help provide novel applications for drugs already under experimentation and open a wide array of opportunities for new drug discovery.

Keywords:  bone marrow microenvironment; chemotherapy resistance; hematology; immune microenvironment; mesenchymal stromal cells

DOI:  https://doi.org/10.3390/cancers13215319
Cancers (Basel). 2021 Nov 02. pii: 5511. [Epub ahead of print]13(21):

Oncogene-Induced Reprogramming in Acute Lymphoblastic Leukemia: Towards Targeted Therapy of Leukemia-Initiating Cells.

Vincent Fregona, Manon Bayet, Bastien Gerby.

  Our understanding of the hierarchical structure of acute leukemia has yet to be fully translated into therapeutic approaches. Indeed, chemotherapy still has to take into account the possibility that leukemia-initiating cells may have a distinct chemosensitivity profile compared to the bulk of the tumor, and therefore are spared by the current treatment, causing the relapse of the disease. Therefore, the identification of the cell-of-origin of leukemia remains a longstanding question and an exciting challenge in cancer research of the last few decades. With a particular focus on acute lymphoblastic leukemia, we present in this review the previous and current concepts exploring the phenotypic, genetic and functional heterogeneity in patients. We also discuss the benefits of using engineered mouse models to explore the early steps of leukemia development and to identify the biological mechanisms driving the emergence of leukemia-initiating cells. Finally, we describe the major prospects for the discovery of new therapeutic strategies that specifically target their aberrant stem cell-like functions.

Keywords:  (pre-)leukemic stem cells; acute lymphoblastic leukemia; cell plasticity; oncogene-induced reprogramming; oncogenic transcription factors; self-renewal

DOI:  https://doi.org/10.3390/cancers13215511
Nat Commun. 2021 Nov 11. 12(1): 6546

Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy.

Steven Ngo, Ethan P Oxley, Margherita Ghisi, Maximilian M Garwood, Mark D McKenzie, Helen L Mitchell, Peter Kanellakis, Olivia Susanto, Michael J Hickey, Andrew C Perkins, Benjamin T Kile, Ross A Dickins.

Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.

DOI: https://doi.org/10.1038/s41467-021-26849-w
FASEB J. 2021 Dec;35(12): e21991

The role of mitochondria in cellular senescence.

Shohini K Ghosh-Choudhary, Jie Liu, Toren Finkel.

  Mitochondria are intimately connected to cell fate and function. Here, we review how these intracellular organelles participate in the induction and maintenance of the senescent state. In particular, we discuss how alterations in mitochondrial metabolism, quality control and dynamics are all involved in various aspects of cellular senescence. Together, these observations suggest that mitochondria are active participants and are mechanistically linked to the unique biology of senescence. We further describe how these insights can be potentially exploited for therapeutic benefit.

Keywords:  aging; metabolism; mitophagy; reactive oxygen species; senolytic

DOI:  https://doi.org/10.1096/fj.202101462R
Exp Hematol. 2021 Nov 09. pii: S0301-472X(21)00424-0. [Epub ahead of print]

Cotargeting of Bcl-2 and Mcl-1 Shows Promising Antileukemic Activity against AML Cells Including those with Acquired Cytarabine Resistance.

Fangbing Liu, Qiushi Zhao, Yongwei Su, Jing Lv, Yuqing Gai, Shuang Liu, Hai Lin, Yue Wang, Guan Wang.

  Acute myeloid leukemia (AML) remains a clinical challenge. Venetoclax is an effective Bcl-2 selective inhibitor approved by the US FDA for treating AML in patients 75 years or older or who have comorbidities. However, resistance to venetoclax limits its clinical efficacy. Mcl-1 has been identified as one determinant of resistance to venetoclax treatment. In this study, we investigate the Mcl-1 inhibitor S63845 in combination with venetoclax in AML cells. We found that S63845 synergizes with venetoclax in AML cell lines and primary patient samples. Bak/Bax double knockdown and treatment with the pan-caspase inhibitor Z-VAD-FMK demonstrate that the combination induces intrinsic apoptosis in AML cells. Inhibition of Mcl-1 using another Mcl-1 selective inhibitor, AZD5991, also synergistically enhanced apoptosis induced by venetoclax in a caspase dependent manner. Importantly, S63845 in combination with venetoclax can effectively combat AML cells with acquired resistance to the standard chemotherapy drug cytarabine. Taken together, combined inhibition of Mcl-1 and Bcl-2 shows promise against AML cells, including relapse/refractory AML.

Keywords:  Bcl-2; Mcl-1; Mcl-1 inhibitor; acute myeloid leukemia; venetoclax

DOI:  https://doi.org/10.1016/j.exphem.2021.10.006
Nat Commun. 2021 Nov 08. 12(1): 6436

Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.

Nadia El Khawanky, Amy Hughes, Wenbo Yu, Renier Myburgh, Tony Matschulla, Sanaz Taromi, Konrad Aumann, Jade Clarson, Janaki Manoja Vinnakota, Khalid Shoumariyeh, Cornelius Miething, Angel F Lopez, Michael P Brown, Justus Duyster, Lutz Hein, Markus G Manz, Timothy P Hughes, Deborah L White, Agnes S M Yong, Robert Zeiser.

Successful treatment of acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) T cells is hampered by toxicity on normal hematopoietic progenitor cells and low CAR T cell persistence. Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3ζ intracellular signaling domain. This CAR demonstrates anti-AML activity without affecting the healthy hematopoietic system, or causing epithelial tissue damage in a xenograft model. CD123 expression on leukemia cells increases upon 5'-Azacitidine (AZA) treatment. AZA treatment of leukemia-bearing mice causes an increase in CTLA-4negative anti-CD123 CAR T cell numbers following infusion. Functionally, the CTLA-4negative anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNFα production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4negative anti-CD123 CAR T cells.

DOI: https://doi.org/10.1038/s41467-021-26683-0