bims-almceb 2021-08-01 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–08–01
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies.
MDVs to the rescue: How autophagy-deficient cancer cells adapt to defective mitophagy.
Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer.
Proteases Regulate Cancer Stem Cell Properties and Remodel Their Microenvironment.
Two transition states of the glycogen shunt and two steady states of gene expression support metabolic flexibility and the Warburg effect in cancer.
HPIP protooncogene differentially regulates metabolic adaptation and cell fate in breast cancer cells under glucose stress via AMPK and RNF2 dependent pathways.
BCL2 inhibitors and MCL1 inhibitors for hematological malignancies.
Ferroptosis in the tumor microenvironment: perspectives for immunotherapy.
ClonMapper Isolates and Characterizes Clones Causing Treatment Resistance.
Small molecule inhibition of deubiquitinating enzyme JOSD1 as a novel targeted therapy for leukemias with mutant JAK2.
Overexpression of CD200 is a Stem Cell-Specific Mechanism of Immune Evasion in AML.

Front Oncol. 2021 ;11 697894

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies.

Guofeng Ma, Chun Li, Zhilei Zhang, Ye Liang, Zhijuan Liang, Yuanbin Chen, Liping Wang, Dan Li, Manqin Zeng, Wenhong Shan, Haitao Niu.

  Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tumor immune escape. Generally, the limited amount of metabolites in the tumor microenvironment leads to nutritional competition between tumors and immune cells. Metabolism regulates tumor cell expression of PD-L1, and the PD-1/PD-L1 immune checkpoint regulates the metabolism of tumor and T cells, which suggests that targeted tumor metabolism may have a synergistic therapeutic effect together with immunotherapy. However, the targeting of different metabolic pathways in different tumors may have different effects on tumor immune escape. Herein, we discuss the influence of glucose metabolism and glutamine metabolism on tumor immune escape and describe the theoretical basis for strategies targeting glucose or glutamine metabolism in combination with PD-1/PD-L1 checkpoint blockade immunotherapy.

Keywords:  PD-1/PD-L1 immune checkpoint; combination therapy; glucose metabolism; glutamine metabolism; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.697894
Dev Cell. 2021 Jul 26. pii: S1534-5807(21)00529-3. [Epub ahead of print]56(14): 2010-2012

MDVs to the rescue: How autophagy-deficient cancer cells adapt to defective mitophagy.

Laura Poillet-Perez, Eileen White.

Cancers are dependent on mitochondria, the powerhouse of the cell, and autophagy, the mechanism to preserve mitochondrial quality and function. In this issue of Developmental Cell, Towers et al. identify mitochondria-derived vesicles (MDVs) as a new adaptive mechanism enabling cancer cells to compensate for autophagy loss and to maintain mitochondrial function.

DOI: https://doi.org/10.1016/j.devcel.2021.06.022
Cancer Drug Resist. 2021 ;4 684-709

Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer.

Haiyun Zhang, Alexander Steed, Milo Co, Xiaozhuo Chen.

  The cancer stem cell (CSC) state and epithelial-mesenchymal transition (EMT) activation are tightly interconnected. Cancer cells that acquire the EMT/CSC phenotype are equipped with adaptive metabolic changes to maintain low reactive oxygen species levels and stemness, enhanced drug transporters, anti-apoptotic machinery and DNA repair system. Factors present in the tumor microenvironment such as hypoxia and the communication with non-cancer stromal cells also promote cancer cells to enter the EMT/CSC state and display related resistance. ATP, particularly the high levels of intratumoral extracellular ATP functioning through both signaling pathways and ATP internalization, induces and regulates EMT and CSC. The three of them work together to enhance drug resistance. New findings in each of these factors will help us explore deeper into mechanisms of drug resistance and suggest new resistance-associated markers and therapeutic targets.

Keywords:  ABC transporters; ATP internalization; Tumor microenvironment; apoptosis; biological markers; macropinocytosis

DOI:  https://doi.org/10.20517/cdr.2021.32
J Histochem Cytochem. 2021 Jul 26. 221554211035192

Proteases Regulate Cancer Stem Cell Properties and Remodel Their Microenvironment.

Anamarija Habič, Metka Novak, Bernarda Majc, Tamara Lah Turnšek, Barbara Breznik.

  Proteolytic activity is perturbed in tumors and their microenvironment, and proteases also affect cancer stem cells (CSCs). CSCs are the therapy-resistant subpopulation of cancer cells with tumor-initiating capacity that reside in specialized tumor microenvironment niches. In this review, we briefly summarize the significance of proteases in regulating CSC activities with a focus on brain tumor glioblastoma. A plethora of proteases and their inhibitors participate in CSC invasiveness and affect intercellular interactions, enhancing CSC immune, irradiation, and chemotherapy resilience. Apart from their role in degrading the extracellular matrix enabling CSC migration in and out of their niches, we review the ability of proteases to modulate CSC properties, which prevents their elimination. When designing protease-oriented therapies, the multifaceted roles of proteases should be thoroughly investigated.

Keywords:  angiogenesis; cancer; cancer stem cells; epithelial-to-mesenchymal transition; glioblastoma; invasion; proteases; stemness; tissue niches; tumor heterogeneity; tumor immune infiltrate; tumor microenvironment

DOI:  https://doi.org/10.1369/00221554211035192
Neoplasia. 2021 Jul 21. pii: S1476-5586(21)00046-4. [Epub ahead of print]23(9): 879-886

Two transition states of the glycogen shunt and two steady states of gene expression support metabolic flexibility and the Warburg effect in cancer.

Douglas L Rothman, Robert G Shulman.

  Previously we suggested that the early Warburg effect can be explained by the use by cancer cells the glycogen shunt during a rapid increase in glucose concentration. In analogy to the Crabtree effect in yeast, the shunt plays a critical role in maintaining homeostasis of glycolytic intermediate levels during these transitions. We extend this analysis here, and propose that the recently appreciated flexibility of cancer cell glucose and glycogen metabolism involves 4 metabolic states that we recently identified in metabolic control analysis studies of yeast. Under stable conditions of low glucose and normal O2 yeast, and by analogy cancer, cells are in the Respiration State in which through gene expression for oxidizing non glucose substrates. When their environment changes to high glucose with reduced O2 levels, such as occur in tumors, they transition to the Glycolysis State due to gene expression of new glycolytic enzyme isoforms such as PKM2. These isoforms optimize metabolism to sustain the Warburg effect. When the changes in glucose and O2 levels are rapid there may be insufficient time for gene expression to adapt. The metabolic flexibility conferred by 2 states of the glycogen shunt allow the cells to survive these transitions. The model explains experimental observations in cancer such as the function of the glycogen shunt and the frequent expression of PKM2 in cells undergoing the Warburg Effect. A surprising conclusion is that the function of PKM2 is to maintain glycolytic intermediate homeostasis rather than controlling the glycolytic flux. The glycogen shunt may also have an important role in cancer metabolic reprogramming by allowing cancer cells to survive large glucose and oxygen changes during the selection of mutations that lead to the Warburg phenotype.

Keywords:  Glycogen Shunt; Homeostasis; Metabolic Flexibility; Oncogenesis; Warburg Effect

DOI:  https://doi.org/10.1016/j.neo.2021.06.004
Cancer Lett. 2021 Jul 22. pii: S0304-3835(21)00354-2. [Epub ahead of print]518 243-255

HPIP protooncogene differentially regulates metabolic adaptation and cell fate in breast cancer cells under glucose stress via AMPK and RNF2 dependent pathways.

Vasudevarao Penugurti, Saratchandra Singh Khumukcham, Chiranjeevi Padala, Anju Dwivedi, Karthik Reddy Kamireddy, Srinivasulu Mukta, Triveni Bhopal, Bramanandam Manavathi.

  While cancer cells rewire metabolic pathways to sustain growth and survival under metabolic stress in solid tumors, the molecular mechanisms underlying these processes remain largely unknown. In this study, cancer cells switched from survival to death during the early to late phases of metabolic stress by employing a novel signaling switch from AMP activated protein kinase (AMPK)-Forkhead box O3 (FOXO3a)-hematopoietic PBX1-interacting protein (HPIP) to the ring finger protein 2 (RNF2)-HPIP-ubiquitin (Ub) pathway. Acute metabolic stress induced proto-oncogene HPIP expression in an AMPK-FOXO3a-dependent manner in breast cancer (BC) cells. HPIP depletion reduced cell survival and tumor formation in mouse xenografts, which was accompanied by diminished intracellular ATP levels and increased apoptosis in BC cells in response to metabolic (glucose) stress. Glutamine flux (13C-labeled) analysis further suggested that HPIP rewired glutamine metabolism by controlling the expression of the solute carrier family 1 member 5 (SLC1A5) and glutaminase (GLS) genes by acting as a coactivator of MYC to ensure cell survival upon glucose deprivation. However, in response to chronic glucose stress, HPIP was ubiquitinated by the E3-Ub ligase, RNF2, and was concomitantly degraded by the proteasome-mediated pathway, ensuring apoptosis. In support of these data, clinical analyses further indicated that elevated levels of HPIP correlated with AMPK activation in BC. Taken together, these data suggest that HPIP is a signal coordinator during metabolic stress and thus serves as a potential therapeutic target in BC.

Keywords:  AMPK; Apoptosis; Cell survival; FOXO3a; Glutaminolysis; HPIP; MYC

DOI:  https://doi.org/10.1016/j.canlet.2021.07.027
Blood. 2021 Jul 28. pii: blood.2020006785. [Epub ahead of print]

BCL2 inhibitors and MCL1 inhibitors for hematological malignancies.

Andrew W Roberts, Andrew H Wei, David Ching Siang Huang.

BCL2 and MCL1 are commonly expressed pro-survival (anti-apoptotic) proteins in hematological cancers and play important roles in their biology either through dysregulation or by virtue of intrinsic importance to the cell-of-origin of the malignancy. A new class of small molecule anti-cancer drugs, BH3-mimetics, now enable specific targeting of these proteins in patients. BH3-mimetics act by inhibiting the pro-survival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors which permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other anti-neoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia (CLL) and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3-mimetics are better suited to limited-duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3-mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several non-hematological tissues.

DOI: https://doi.org/10.1182/blood.2020006785
Trends Mol Med. 2021 Jul 23. pii: S1471-4914(21)00181-7. [Epub ahead of print]

Ferroptosis in the tumor microenvironment: perspectives for immunotherapy.

Huanji Xu, Di Ye, Meiling Ren, Hongying Zhang, Feng Bi.

  Targeting ferroptosis, which provokes lipid peroxidation in cancer cells, presents potentially new avenues for anticancer therapy. Recent studies have begun to explore how immune cells in the tumor microenvironment (TME) respond and adapt to lethal lipid peroxides (LPOs). A better understanding of this process in the TME is likely to uncover another side of ferroptosis in cancer immunity and promote the development of ferroptosis-targeted therapy. This Opinion article overviews the main metabolic processes in ferroptosis, summarizes the emerging roles of ferroptosis not only in immune cells in the TME but also in the crosstalk between tumor cells and immune cells, and presents a perspective on the targeting of ferroptosis in cancer immunotherapy.

Keywords:  ferroptosis; immune cells; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.molmed.2021.06.014
Cancer Discov. 2021 Jul 30.

ClonMapper Isolates and Characterizes Clones Causing Treatment Resistance.

Leukemia cell clones that rebound after treatment have differential levels of therapeutic tolerance.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-106
Leukemia. 2021 Jul 29.

Small molecule inhibition of deubiquitinating enzyme JOSD1 as a novel targeted therapy for leukemias with mutant JAK2.

Jing Yang, Ellen L Weisberg, Xiaoxi Liu, Robert S Magin, Wai Cheung Chan, Bin Hu, Nathan J Schauer, Shengzhe Zhang, Ilaria Lamberto, Laura Doherty, Chengcheng Meng, Martin Sattler, Lucia Cabal-Hierro, Eric Winer, Richard Stone, Jarrod A Marto, James D Griffin, Sara J Buhrlage.

Mutations in the Janus Kinase 2 (JAK2) gene resulting in constitutive kinase activation represent the most common genetic event in myeloproliferative neoplasms (MPN), a group of diseases involving overproduction of one or more kinds of blood cells, including red cells, white cells, and platelets. JAK2 kinase inhibitors, such as ruxolitinib, provide clinical benefit, but inhibition of wild-type (wt) JAK2 limits their clinical utility due to toxicity to normal cells, and small molecule inhibition of mutated JAK2 kinase activity can lead to drug resistance. Here, we present a strategy to target mutated JAK2 for degradation, using the cell's intracellular degradation machinery, while sparing non-mutated JAK2. We employed a chemical genetics screen, followed by extensive selectivity profiling and genetic studies, to identify the deubiquitinase (DUB), JOSD1, as a novel regulator of mutant JAK2. JOSD1 interacts with and stabilizes JAK2-V617F, and inactivation of the DUB leads to JAK2-V617F protein degradation by increasing its ubiquitination levels, thereby shortening its protein half-life. Moreover, targeting of JOSD1 leads to the death of JAK2-V617F-positive primary acute myeloid leukemia (AML) cells. These studies provide a novel therapeutic approach to achieving selective targeting of mutated JAK2 signaling in MPN.

DOI: https://doi.org/10.1038/s41375-021-01336-9
J Immunother Cancer. 2021 Jul;pii: e002968. [Epub ahead of print]9(7):

Overexpression of CD200 is a Stem Cell-Specific Mechanism of Immune Evasion in AML.

Shelley Herbrich, Natalia Baran, Tianyu Cai, Connie Weng, Marisa J L Aitken, Sean M Post, Jared Henderson, Chunhua Shi, Guillame Richard-Carpentier, Guy Sauvageau, Keith Baggerly, Gheath Al-Atrash, R Eric Davis, Naval Daver, Dongxing Zha, Marina Konopleva.

   BACKGROUND: Acute myeloid leukemia (AML) stem cells (LSCs) are capable of surviving current standard chemotherapy and are the likely source of deadly, relapsed disease. While stem cell transplant serves as proof-of-principle that AML LSCs can be eliminated by the immune system, the translation of existing immunotherapies to AML has been met with limited success. Consequently, understanding and exploiting the unique immune-evasive mechanisms of AML LSCs is critical.
METHODS: Analysis of stem cell datasets and primary patient samples revealed CD200 as a putative stem cell-specific immune checkpoint overexpressed in AML LSCs. Isogenic cell line models of CD200 expression were employed to characterize the interaction of CD200+ AML with various immune cell subsets both in vitro and in peripheral blood mononuclear cell (PBMC)-humanized mouse models. CyTOF and RNA-sequencing were performed on humanized mice to identify novel mechanisms of CD200-mediated immunosuppression. To clinically translate these findings, we developed a fully humanized CD200 antibody (IgG1) that removed the immunosuppressive signal by blocking interaction with the CD200 receptor while also inducing a potent Fc-mediated response. Therapeutic efficacy of the CD200 antibody was evaluated using both humanized mice and patient-derived xenograft models.
RESULTS: Our results demonstrate that CD200 is selectively overexpressed in AML LSCs and is broadly immunosuppressive by impairing cytokine secretion in both innate and adaptive immune cell subsets. In a PBMC-humanized mouse model, CD200+ leukemia progressed rapidly, escaping elimination by T cells, compared with CD200- AML. T cells from mice with CD200+ AML were characterized by an abundance of metabolically quiescent CD8+ central and effector memory cells. Mechanistically, CD200 expression on AML cells significantly impaired OXPHOS metabolic activity in T cells from healthy donors. Importantly, CD200 antibody therapy could eliminate disease in the presence of graft-versus-leukemia in immune competent mice and could significantly improve the efficacy of low-intensity azacitidine/venetoclax chemotherapy in immunodeficient hosts.
CONCLUSIONS: Overexpression of CD200 is a stem cell-specific marker that contributes to immunosuppression in AML by impairing effector cell metabolism and function. CD200 antibody therapy is capable of simultaneously reducing CD200-mediated suppression while also engaging macrophage activity. This study lays the groundwork for CD200-targeted therapeutic strategies to eliminate LSCs and prevent AML relapse.

Keywords:  immunomodulation; lymphocyte activation; metabolic networks and pathways; tumor escape

DOI:  https://doi.org/10.1136/jitc-2021-002968