bims-almceb 2022-01-30 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–01–30
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells.
Mitochondrial biogenesis gene POLG correlates with outcome in pediatric acute myeloid leukemia.
RNA-binding proteins as drivers of AML and novel therapeutic targets.
Circadian control of mitochondria in ROS homeostasis.
Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1.
Relationship between leukaemic stem cells and hematopoietic stem cells and their clinical application.
A Metabolic Reprogramming Amino Acid Polymer as an Immunosurveillance Activator and Leukemia Targeting Drug Carrier for T-Cell Acute Lymphoblastic Leukemia.
The mixed blessing of AMPK signaling in Cancer treatments.
Associating Drug Sensitivity with Differentiation Status Identifies Effective Combinations for Acute Myeloid Leukemia.
Combining Isocitrate Dehydrogenase Inhibitors With Existing Regimens in Acute Myeloid Leukemia: An Evolving Treatment Landscape.
Monoclonal Antibodies in Acute Myeloid Leukemia-Are We There Yet?

Dev Cell. 2022 Jan 24. pii: S1534-5807(21)01040-6. [Epub ahead of print]57(2): 260-276.e9

Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells.

Rani Ojha, Ishaq Tantray, Suman Rimal, Siddhartha Mitra, Sam Cheshier, Bingwei Lu.

  Metabolic flexibility is a hallmark of many cancers where mitochondrial respiration is critically involved, but the molecular underpinning of mitochondrial control of cancer metabolic reprogramming is poorly understood. Here, we show that reverse electron transfer (RET) through respiratory chain complex I (RC-I) is particularly active in brain cancer stem cells (CSCs). Although RET generates ROS, NAD+/NADH ratio turns out to be key in mediating RET effect on CSC proliferation, in part through the NAD+-dependent Sirtuin. Mechanistically, Notch acts in an unconventional manner to regulate RET by interacting with specific RC-I proteins containing electron-transporting Fe-S clusters and NAD(H)-binding sites. Genetic and pharmacological interference of Notch-mediated RET inhibited CSC growth in Drosophila brain tumor and mouse glioblastoma multiforme (GBM) models. Our results identify Notch as a regulator of RET and RET-induced NAD+/NADH balance, a critical mechanism of metabolic reprogramming and a metabolic vulnerability of cancer that may be exploited for therapeutic purposes.

Keywords:  NAD(+)/NADH; Sirtuin; Warburg effect; glioblastoma multiforme; inflammation; metabolic reprogramming; mitochondrial complex I; non-canonical Notch signaling; reactive oxygen species; reverse electron transport

DOI:  https://doi.org/10.1016/j.devcel.2021.12.020
Leuk Lymphoma. 2022 Jan 25. 1-4

Mitochondrial biogenesis gene POLG correlates with outcome in pediatric acute myeloid leukemia.

Shilpi Chaudhary, Shuvadeep Ganguly, Archna Singh, Jayanth Kumar Palanichamy, Radhika Bakhshi, Anita Chopra, Sameer Bakhshi.

DOI: https://doi.org/10.1080/10428194.2021.2010063
Leuk Lymphoma. 2022 Jan 25. 1-13

RNA-binding proteins as drivers of AML and novel therapeutic targets.

Tingyu Qin, Ying Cheng, Xiaozhong Wang.

  Acute myeloid leukemia (AML) is a group of genetically complex and heterogeneous invasive hematological malignancies with a low 5-year overall survival rate of 30%, which highlights the urgent need for improved treatment measures. RNA-binding proteins (RBPs) regulate the abundance of isoforms of related proteins by regulating RNA splicing, translation, stability, and localization, thereby affecting cell differentiation and self-renewal. It is increasingly believed that RBPs are essential for normal hematopoiesis, and RBPs play a key role in hematological tumors, especially AML, by acting as oncogenes or tumor suppressors. In addition, targeting an RBP that is significantly related to AML can trigger the apoptosis of leukemic stem cells or promote the proliferation of stem and progenitor cells by modulating the expression of important pathway regulatory factors such as HOXA9, MYC, and CDKN1A. Accordingly, RBPs involved in normal myeloid differentiation and the occurrence of AML may represent promising therapeutic targets.

Keywords:  Acute myeloid leukemia; RNA-binding protein; oncogenes; therapy; tumor suppressors

DOI:  https://doi.org/10.1080/10428194.2021.2008381
Antioxid Redox Signal. 2022 Jan 24.

Circadian control of mitochondria in ROS homeostasis.

Volha Mezhnina, Oghogho P Ebeigbe, Allan Poe, Roman V Kondratov.

SIGNIFICANCE: Mitochondria produce most of the cellular ATP through the process of oxidative phosphorylation. Energy metabolism in the mitochondria is associated with the production of reactive oxygen species (ROS). Excessive ROS production leads to oxidative stress and compromises cellular physiology. Energy metabolism in the mitochondria depends on nutrient flux and cellular metabolic needs, which are in turn connected with the feeding/fasting cycle. In animals, the feeding/fasting cycle is controlled by the circadian clock that generates 24-hour rhythms in behavior, metabolism and signaling. Recent Advances. Here, we discuss the role of the circadian clock and rhythms in mitochondria on ROS homeostasis. Circadian clock is involved in mitochondrial ROS production and detoxification through control of nutrient flux and oxidation, uncoupling, antioxidant defense and mitochondrial dynamics.
CRITICAL ISSUES: Little is known on molecular mechanisms of circadian control of mitochondria functions. The circadian clock regulates the expression and activity of mitochondrial metabolic and antioxidant enzymes. The regulation involves a direct transcriptional control by CLOCK/BMAL1, NRF2 transcriptional network and sirtuin dependent posttranslational protein modifications. Future Perspectives. We hypothesize that the circadian clock orchestrates mitochondria physiology to synchronize it with the feeding/fasting cycle. Circadian coordination of mitochondrial function couples energy metabolism with diets and contributes to antioxidant defense to prevent metabolic diseases and delay aging.

DOI: https://doi.org/10.1089/ars.2021.0274
Front Oncol. 2021 ;11 777587

Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1.

Stefania Fiorcari, Rossana Maffei, Claudio Giacinto Atene, Nicolò Mesini, Monica Maccaferri, Giovanna Leonardi, Silvia Martinelli, Ambra Paolini, Vincenzo Nasillo, Giulia Debbia, Leonardo Potenza, Mario Luppi, Roberto Marasca.

  Chronic lymphocytic leukemia (CLL) has experienced a clinical revolution-thanks to the discovery of crucial pathogenic mechanisms. CLL is still an incurable disease due to intrinsic or acquired resistance of the leukemic clone. Venetoclax is a Bcl-2 inhibitor with a marked activity in CLL, but emerging patterns of resistance are being described. We hypothesize that intrinsic features of CLL cells may contribute to drive mechanisms of resistance to venetoclax. We analyzed the expression of Interferon Regulatory Factor 4 (IRF4), Notch2, and Mcl-1 in a cohort of CLL patients. We evaluated CLL cell viability after genetic and pharmaceutical modulation of Notch2 expression in patients harboring trisomy 12. We tested venetoclax in trisomy 12 CLL cells either silenced or not for Notch2 expression or in combination with an inhibitor of Mcl-1, AMG-176. Trisomy 12 CLL cells were characterized by low expression of IRF4 associated with high levels of Notch2 and Mcl-1. Notch2 and Mcl-1 expression determined protection of CLL cells from spontaneous and drug-induced apoptosis. Considering the involvement of Mcl-1 in venetoclax resistance, our data demonstrated a contribution of high levels of Notch2 and Mcl-1 in a reduced response to venetoclax in CLL cells carrying trisomy 12. Furthermore, reduction of Mcl-1 expression by silencing Notch2 or by treatment with AMG-176 was able to restore the response of CLL cells to venetoclax. The expression of Notch2 identifies a subset of CLL patients, mainly harboring trisomy 12, characterized by high levels of Mcl-1. This biological mechanism may compromise an effective response to venetoclax.

Keywords:  Notch; chronic lymphocytic leukemia (CLL); drug resistance; translational research; venetoclax (ABT-199)

DOI:  https://doi.org/10.3389/fonc.2021.777587
Leuk Lymphoma. 2022 Jan 22. 1-10

Relationship between leukaemic stem cells and hematopoietic stem cells and their clinical application.

Samuel S Y Wang.

  The world is aging and with it an associated increase in malignancies. Haematological malignancies especially Acute Myeloid Leukemia (AML) are no exception to this trend. With scientific advances, development of new AML treatments has improved patient mortality. One future research interest would be Leukeamic Stem Cells (LSC). This review aims to briefly highlight main LSC characteristics and their relationship with hematopoietic stem cells. Key LSC characteristics include dysregulated apoptosis, capacity for self-renewal, genomic instability, dysregulated energetics, immune privilege and an altered tumor microenvironment. Similar characteristics are also found in HSCs though in a regulated form. Classifying these characteristics will aid in the development of clinical biomarkers for LSC which is a potential clinical application of LSC biology. LSC biomarkers might prove to be critical in future AML management through improving accuracy of AML diagnosis, providing targeted treatment to minimize side effects, refinement of prognosis and relapse risk for earlier intervention.

Keywords:  Acute myeloid leukemia; hematopoeitic stem cells; leukaemic stem cells

DOI:  https://doi.org/10.1080/10428194.2022.2027401
Adv Sci (Weinh). 2022 Jan 26. e2104134

A Metabolic Reprogramming Amino Acid Polymer as an Immunosurveillance Activator and Leukemia Targeting Drug Carrier for T-Cell Acute Lymphoblastic Leukemia.

Changzheng Li, Xinru You, Xi Xu, Binghuo Wu, Yuye Liu, Tong Tong, Jie Chen, Yishan Li, Chunlei Dai, Zhitao Ye, Xiaobin Tian, Yan Wei, Zechen Hao, Linjia Jiang, Jun Wu, Meng Zhao.

  Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting-therapy efficacy remains unexplored. Here, an L-phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T-cell acute lymphoblastic leukemia (T-ALL) by inhibiting myeloid-derived suppressor cells (MDSCs) in T-ALL murine model. Stable-isotope tracer and in vivo drug distribution experiments show that T-ALL cells and MDSCs have enhanced cellular uptake of L-phenylalanine and MRIANs than normal hematopoietic cells and progenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN-Dox) specifically targets T-ALL cells and MDSCs but spare normal hematopoietic cells and hematopoietic stem and progenitor cells with enhanced leukemic elimination efficiency. Consequently, MRIAN-Dox has reduced cardiotoxicity and myeloablation side effects in treating T-ALL mice. Mechanistically, MRIAN degrades into L-phenylalanine, which inhibits PKM2 activity and reduces ROS levels in MDSCs to disturb their immunosuppressive function and increase their differentiation toward normal myeloid cells. Overall, a novel amino acid metabolite nanomedicine is invented to treat T-ALL through the combination of leukemic cell targeting and immunosurveillance stimulation.

Keywords:  Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN); T-cell acute lymphoblastic leukemia (T-ALL); amino acid metabolism; immunosurveillance; myeloid-derived suppressor cells (MDSCs)

DOI:  https://doi.org/10.1002/advs.202104134
BMC Cancer. 2022 Jan 25. 22(1): 105

The mixed blessing of AMPK signaling in Cancer treatments.

Mehrshad Sadria, Deokhwa Seo, Anita T Layton.

   BACKGROUND: Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands. A major regulator of cellular metabolism and energy homeostasis, in normal and cancer cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation of the mechanistic target of Rapamycin (mTOR) pathway, specifically, by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by activating mTORC2 and cell survival. Given its conflicting roles, the effects of AMPK activation in cancer can be counter intuitive. Prior to the establishment of cancer, AMPK acts as a tumor suppressor. However, following the onset of cancer, AMPK has been shown to either suppress or promote cancer, depending on cell type or state.
METHODS: To unravel the controversial roles of AMPK in cancer, we developed a computational model to simulate the effects of pharmacological maneuvers that target key metabolic signalling nodes, with a specific focus on AMPK, mTORC, and their modulators. Specifically, we constructed an ordinary differential equation-based mechanistic model of AMPK-mTORC signaling, and parametrized the model based on existing experimental data.
RESULTS: Model simulations were conducted to yield the following predictions: (i) increasing AMPK activity has opposite effects on mTORC depending on the nutrient availability; (ii) indirect inhibition of AMPK activity through inhibition of sirtuin 1 (SIRT1) only has an effect on mTORC activity under conditions of low nutrient availability; (iii) the balance between cell proliferation and survival exhibits an intricate dependence on DEP domain-containing mTOR-interacting protein (DEPTOR) abundance and AMPK activity; (iv) simultaneous direct inhibition of mTORC2 and activation of AMPK is a potential strategy for suppressing both cell survival and proliferation.
CONCLUSIONS: Taken together, model simulations clarify the competing effects and the roles of key metabolic signalling pathways in tumorigenesis, which may yield insights on innovative therapeutic strategies.

Keywords:  AMPK; Cancer; Dynamical system; Metabolism; mTORC

DOI:  https://doi.org/10.1186/s12885-022-09211-1
Blood Adv. 2022 Jan 25. pii: bloodadvances.2021006307. [Epub ahead of print]

Associating Drug Sensitivity with Differentiation Status Identifies Effective Combinations for Acute Myeloid Leukemia.

Stephen E Kurtz, Christopher A Eide, Andy Kaempf, Nicola Long, Daniel Bottomly, Olga Nikolova, Brian J Druker, Shannon K McWeeney, Bill H Chang, Jeffrey W Tyner, Anupriya Agarwal.

Using ex vivo drug screening of primary patient specimens, we identified the combination of the p38 MAPK inhibitor doramapimod (DORA) with the BCL2 inhibitor venetoclax (VEN) as demonstrating broad, enhanced efficacy compared to each single agent across 335 AML patient samples while sparing primary stromal cells. Single-agent DORA and VEN sensitivity associated with distinct, non-overlapping tumor cell differentiation states. In particular, increased monocytes, M4/M5 FAB classification, and CD14+ immunophenotype tracked with sensitivity to DORA and resistance to VEN, but were mitigated with the combination. Increased expression of MAPK14 and BCL2, the respective primary targets of DORA and VEN, were observed in monocytic and undifferentiated leukemias, respectively. Enrichment for DORA and VEN sensitivities were observed in AML with monocyte-like and progenitor-like transcriptomic signatures, respectively, and these associations diminished with the combination. The mechanism underlying the combination's enhanced efficacy may result from inhibition of p38 MAPK-mediated phosphorylation of BCL2, which in turn enhances sensitivity to venetoclax. These findings suggest exploiting complementary drug sensitivity profiles with respect to leukemic differentiation state, such as dual targeting of p38 MAPK and BCL2, offers opportunity for broad, enhanced efficacy across the clinically challenging heterogeneous landscape of AML.

DOI: https://doi.org/10.1182/bloodadvances.2021006307
Cancer J. 2022 Jan-Feb 01;28(1):28(1): 21-28

Combining Isocitrate Dehydrogenase Inhibitors With Existing Regimens in Acute Myeloid Leukemia: An Evolving Treatment Landscape.

Curtis Lachowiez, Courtney D DiNardo, Etyan Stein.

ABSTRACT: Identification of recurrent mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) in patients with acute myeloid leukemia (AML) coupled with an understanding of the pathologic role these mutant IDH isoforms impart in leukemogenesis resulted in the development of IDH1 and IDH2 inhibitors comprising a novel, molecularly defined class of targeted therapies for the treatment of AML. This review herein describes the unique cellular pathophysiology and vulnerabilities in IDH-mutated AML; the clinical development, efficacy, and known resistance mechanisms to first-generation IDH inhibitors; summarizes the literature surrounding combination therapies incorporating targeted or cytotoxic therapies with IDH inhibitors in patients with IDH-mutated AML; and identifies future challenges and areas of active ongoing investigation within this molecular subgroup.

DOI: https://doi.org/10.1097/PPO.0000000000000570
Cancer J. 2022 Jan-Feb 01;28(1):28(1): 37-42

Monoclonal Antibodies in Acute Myeloid Leukemia-Are We There Yet?

Yasmin Abaza, Amir T Fathi.

ABSTRACT: Despite recent advances in the treatment of acute myeloid leukemia (AML), relapses remain high, and long-term survival is poor, emphasizing the need for better treatment options. Development of targeted antibody-based immunotherapeutic agents has been an area of growing research in AML. Target antigens of interest include CD33, CD123, CD47, CD70, FLT3, and CLL-1 because of their high expression on AML blasts and leukemic stem cells. Gemtuzumab ozogamicin, a CD33-directed antibody-drug conjugate, is the only Food and Drug Administration-approved monoclonal antibody (mAb) in AML providing evidence for the potential future role of mAb-based therapies in AML. This article provides an overview of the progress made in targeted immunotherapy in AML, particularly focusing on unconjugated and conjugated mAbs.

DOI: https://doi.org/10.1097/PPO.0000000000000577