bims-almceb 2021-04-18 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021‒04‒18
twelve papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS.
Jiyuan Oridonin A Overcomes Differentiation Blockade in Acute Myeloid Leukemia Cells With MLL Rearrangements via Multiple Signaling Pathways.
An aged bone marrow niche restrains rejuvenated hematopoietic stem cells.
Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response.
Epigenetic Modifiers: Anti-Neoplastic Drugs With Immunomodulating Potential.
Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling.
The clinical significance of PD‑L1 in colorectal cancer (Review).
Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment.
A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells.
Progesterone Modulates Mitochondrial Functions in Human Glioblastoma Cells.
Integrative study of EZH2 mutational status, copy number, protein expression and H3K27 trimethylation in AML/MDS patients.
Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging.

Mol Cell. 2021 Apr 10. pii: S1097-2765(21)00143-X. [Epub ahead of print]

Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS.

Alexis A Jourdain, Bridget E Begg, Eran Mick, Hardik Shah, Sarah E Calvo, Owen S Skinner, Rohit Sharma, Steven M Blue, Gene W Yeo, Christopher B Burge, Vamsi K Mootha.

  Oxidative phosphorylation (OXPHOS) and glycolysis are the two major pathways for ATP production. The reliance on each varies across tissues and cell states, and can influence susceptibility to disease. At present, the full set of molecular mechanisms governing the relative expression and balance of these two pathways is unknown. Here, we focus on genes whose loss leads to an increase in OXPHOS activity. Unexpectedly, this class of genes is enriched for components of the pre-mRNA splicing machinery, in particular for subunits of the U1 snRNP. Among them, we show that LUC7L2 represses OXPHOS and promotes glycolysis by multiple mechanisms, including (1) splicing of the glycolytic enzyme PFKM to suppress glycogen synthesis, (2) splicing of the cystine/glutamate antiporter SLC7A11 (xCT) to suppress glutamate oxidation, and (3) secondary repression of mitochondrial respiratory supercomplex formation. Our results connect LUC7L2 expression and, more generally, the U1 snRNP to cellular energy metabolism.

Keywords:  7q-; LUC7; MDS; Tarui disease; cancer; ferroptosis; myelodysplastic syndrome; phosphofructokinase; spliceosome; system X(c)(−)

DOI:  https://doi.org/10.1016/j.molcel.2021.02.033
Front Oncol. 2021 ;11 659720

Jiyuan Oridonin A Overcomes Differentiation Blockade in Acute Myeloid Leukemia Cells With MLL Rearrangements via Multiple Signaling Pathways.

Mei Qu, Yu Duan, Min Zhao, Zhanju Wang, Mengjie Zhao, Yao Zhao, Haihua Wang, Yu Ke, Ying Liu, Hong-Min Liu, Liuya Wei, Zhenbo Hu.

  Differentiation therapy with all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), has been extremely successful in inducing clinical remission in APL patients. However, the differentiation therapy of ATRA-based treatment has not been effective in other subtypes of AML. In this study, we evaluated a small molecule of ent-kaurene diterpenoid, Jiyuan oridonin A (JOA), on the differentiation blockade in AML cells with the mixed lineage leukemia (MLL) gene rearrangements (MLLr) in MV4-11, MOLM-13 and THP-1 cells. We found that JOA could significantly inhibit the proliferation of MOLM-13, MV4-11 and THP-1 cells. Moreover, JOA promoted cell differentiation coupled with cell-cycle exit at G0/G1 and inhibited the colony- forming capacity of these cells. We showed that the anti-proliferative effect of JOA attributed to cell differentiation is most likely through the martens tretinoin response up pathway in the MOLM-13 cell line, and the hematopoietic cell lineage pathway by the inhibition of c-KIT expression and cell adhesion pathway in the THP-1 cell line. Our findings suggest that JOA could be a novel therapeutic agent against human MLLr acute myeloid leukemia.

Keywords:  Jiyuan oridonin A; acute myeloid leukemia with MLL gene rearrangements; cell adhesion pathway; differentiation therapy; hematopoietic cell lineage pathway; martens tretinoin response up pathway

DOI:  https://doi.org/10.3389/fonc.2021.659720
Stem Cells. 2021 Apr 13.

An aged bone marrow niche restrains rejuvenated hematopoietic stem cells.

Novella Guidi, Gina Marka, Vadim Sakk, Yi Zheng, Maria Carolina Florian, Hartmut Geiger.

  Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs.

Keywords:  Cdc42; aging; hematopoietic stem cell; niche; osteopontin; rejuvenation

DOI:  https://doi.org/10.1002/stem.3372
Front Cell Dev Biol. 2021 ;9 626117

Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response.

Robert Gilkerson, Patrick De La Torre, Shaynah St Vallier.

  Mammalian mitochondria are emerging as a critical stress-responsive contributor to cellular life/death and developmental outcomes. Maintained as an organellar network distributed throughout the cell, mitochondria respond to cellular stimuli and stresses through highly sensitive structural dynamics, particularly in energetically demanding cell settings such as cardiac and muscle tissues. Fusion allows individual mitochondria to form an interconnected reticular network, while fission divides the network into a collection of vesicular organelles. Crucially, optic atrophy-1 (OPA1) directly links mitochondrial structure and bioenergetic function: when the transmembrane potential across the inner membrane (ΔΨm) is intact, long L-OPA1 isoforms carry out fusion of the mitochondrial inner membrane. When ΔΨm is lost, L-OPA1 is cleaved to short, fusion-inactive S-OPA1 isoforms by the stress-sensitive OMA1 metalloprotease, causing the mitochondrial network to collapse to a fragmented population of organelles. This proteolytic mechanism provides sensitive regulation of organellar structure/function but also engages directly with apoptotic factors as a major mechanism of mitochondrial participation in cellular stress response. Furthermore, emerging evidence suggests that this proteolytic mechanism may have critical importance for cell developmental programs, particularly in cardiac, neuronal, and stem cell settings. OMA1's role as a key mitochondrial stress-sensitive protease motivates exciting new questions regarding its mechanistic regulation and interactions, as well as its broader importance through involvement in apoptotic, stress response, and developmental pathways.

Keywords:  OMA1; OPA1; apoptosis; development; mitochondria

DOI:  https://doi.org/10.3389/fcell.2021.626117
Front Immunol. 2021 ;12 652160

Epigenetic Modifiers: Anti-Neoplastic Drugs With Immunomodulating Potential.

Ken Maes, Anna Mondino, Juan José Lasarte, Xabier Agirre, Karin Vanderkerken, Felipe Prosper, Karine Breckpot.

  Cancer cells are under the surveillance of the host immune system. Nevertheless, a number of immunosuppressive mechanisms allow tumors to escape protective responses and impose immune tolerance. Epigenetic alterations are central to cancer cell biology and cancer immune evasion. Accordingly, epigenetic modulating agents (EMAs) are being exploited as anti-neoplastic and immunomodulatory agents to restore immunological fitness. By simultaneously acting on cancer cells, e.g. by changing expression of tumor antigens, immune checkpoints, chemokines or innate defense pathways, and on immune cells, e.g. by remodeling the tumor stroma or enhancing effector cell functionality, EMAs can indeed overcome peripheral tolerance to transformed cells. Therefore, combinations of EMAs with chemo- or immunotherapy have become interesting strategies to fight cancer. Here we review several examples of epigenetic changes critical for immune cell functions and tumor-immune evasion and of the use of EMAs in promoting anti-tumor immunity. Finally, we provide our perspective on how EMAs could represent a game changer for combinatorial therapies and the clinical management of cancer.

Keywords:  cancer; epigenetics; immune evasion; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2021.652160
Mol Med. 2021 Apr 13. 27(1): 38

Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling.

Jing Cui, Yao Guo, Heshui Wu, Jiongxin Xiong, Tao Peng.

  BACKGROUND: Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer.METHODS: The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEMsen) and GEM-resistant (GEMres) pancreatic cancer cells.
RESULTS: We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEMsen and GEMres cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEMres cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEMres cells than that in GEMsen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEMres tumors, Evr significantly decreased the volume of GEMres tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM.
CONCLUSIONS: Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.

Keywords:  Drug resistance; Everolimus; Gemcitabine; Metabolism; Pancreatic cancer

DOI:  https://doi.org/10.1186/s10020-021-00300-8
Oncol Rep. 2021 Jun;pii: 92. [Epub ahead of print]45(6):

The clinical significance of PD‑L1 in colorectal cancer (Review).

Vasileia Ntomi, Periklis Foukas, Dimitrios Papaconstantinou, Ioanna Antonopoulou, Andreas Pikoulis, Ioannis Panagiotides, Emmanouil Pikoulis, Konstantinos Syrigos.

Colorectal cancer (CRC) is one of the most frequently encountered neoplasms and has a high rate of morbidity and mortality. Recent findings showing that tumor immune evasion is an important mechanism underlying propagation of a cancer have changed the landscape of medical oncology through identification of Programmed‑Death receptor 1 and its ligand (PD‑1 and PD‑L1) as novel targets for oncological immune therapies. PD‑1 is primarily expressed on peritumoral lymphocytes and when activated, it suppresses its immune functions. Conversely, PD‑L1 is primarily expressed on the tumor infiltrating front with the purpose of deregulating physiological cytotoxic immune responses. Numerous studies have linked PD‑L1 overexpression to specific adverse clinicopathological features, such as poor differentiation, lymphovascular invasion and worse overall survival in CRC patients. Nevertheless, there is no concrete evidence showing which patients may exhibit the maximal beneficial effects of PD‑1/PD‑L1 blockade therapy, and how these novel molecular targets may be optimally integrated into therapeutic regimens for management of CRC patients with resectable and generalized disease.

DOI: https://doi.org/10.3892/or.2021.8043
Cell Metab. 2021 Apr 10. pii: S1550-4131(21)00130-3. [Epub ahead of print]

Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment.

Sophie M Poznanski, Kanwaldeep Singh, Tyrah M Ritchie, Jennifer A Aguiar, Isabella Y Fan, Ana L Portillo, Eduardo A Rojas, Fatemeh Vahedi, Abdullah El-Sayes, Sansi Xing, Martin Butcher, Yu Lu, Andrew C Doxey, Jonathan D Schertzer, Hal W Hirte, Ali A Ashkar.

  NK cells are central to anti-tumor immunity and recently showed efficacy for treating hematologic malignancies. However, their dysfunction in the hostile tumor microenvironment remains a pivotal barrier for cancer immunotherapies against solid tumors. Using cancer patient samples and proteomics, we found that human NK cell dysfunction in the tumor microenvironment is due to suppression of glucose metabolism via lipid peroxidation-associated oxidative stress. Activation of the Nrf2 antioxidant pathway restored NK cell metabolism and function and resulted in greater anti-tumor activity in vivo. Strikingly, expanded NK cells reprogrammed with complete metabolic substrate flexibility not only sustained metabolic fitness but paradoxically augmented their tumor killing in the tumor microenvironment and in response to nutrient deprivation. Our results uncover that metabolic flexibility enables a cytotoxic immune cell to exploit the metabolic hostility of tumors for their advantage, addressing a critical hurdle for cancer immunotherapy.

Keywords:  NK cell metabolism; NK cells; Warburg effect; adoptive cell therapy; cancer immunotherapy; glucose metabolism; immunometabolism; metabolic flexibility; oxidative stress; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cmet.2021.03.023
Cancer Lett. 2021 Apr 13. pii: S0304-3835(21)00157-9. [Epub ahead of print]

A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells.

Yinghui Li, Yafang Li, Jingjing Yin, Chaoqun Wang, Ming Yang, Jiali Gu, Mei He, Hui Xu, Weichao Fu, Wenshan Zhang, Yongxin Ru, Xiaolei Liu, Ying Li, Yue Xin, Huier Gao, Xiangqun Xie, Yingdai Gao.

  There has been an increasing focus on the tumorigenic potential of leukemia initiating cells (LICs) in acute myeloid leukemia (AML). Despite the important role of selective autophagy in the life-long maintenance of hematopoietic stem cells (HSCs), cancer progression, and chemoresistance, the relationship between LICs and selective autophagy remains to be fully elucidated. Sequestosome 1 (SQSTM1), also known as p62, is a selective autophagy receptor for the degradation of ubiquitinated substrates, and its loss impairs leukemia progression in AML mouse models. In this study, we evaluated the underlying mechanisms of mitophagy in the survival of LICs with XRK3F2, a p62-ZZ inhibitor. We demonstrated that XRK3F2 selectively impaired LICs but spared normal HSCs in both mouse and patient-derived tumor xenograft (PDX) AML models. Mechanistically, we observed that XRK3F2 blocked mitophagy by inhibiting the binding of p62 with defective mitochondria. Our study not only evaluated the effectiveness and safety of XRK3F2 in LICs, but also demonstrated that mitophagy plays an indispensable role in the survival of LICs during AML development and progression, which can be impaired by blocking p62.

Keywords:  AML; Autophagy; LICs; Small molecular compound

DOI:  https://doi.org/10.1016/j.canlet.2021.04.003
Mol Neurobiol. 2021 Apr 13.

Progesterone Modulates Mitochondrial Functions in Human Glioblastoma Cells.

Fahim Atif, Seema Yousuf, Claudia Espinosa-Garcia, Donald G Stein.

  A substantial literature supports the notion that cancer is a metabolic disease. Mitochondria are sexually dimorphic, and progesterone (P4) plays a key regulatory role in mitochondrial functions. We investigated the effect of P4 on mitochondrial functions in three human glioblastoma multiforme (GBM) cell lines. In dose-response and time-response studies, GBM cells were exposed to different concentrations of P4 followed by mitochondrial stress-testing with a Seahorse analyzer. Data were analyzed for oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and spare respiratory capacity (SRC) to determine the effects of P4 exposure on mitochondrial respiration and rate of glycolysis. We also examined the effect of P4 on mitochondrial superoxide radical generation by confocal microscopy. As early as 1h post-P4 exposure, we found a substantial dose-dependent inhibitory effect of P4 on OCR, ECAR, and SRC in all GBM cell lines. P4 treatment altered the levels of basal respiration, maximum respiration, nonmitochondrial oxygen consumption, ATP production, and proton leak. P4 given at 80-μM concentration showed the maximum inhibitory effect compared to controls. Live imaging data showed an 11-22% increase in superoxide radical generation in all three GBM cell lines following 6h exposure to a high concentration of P4. Our data show that high-dose P4 exerts an inhibitory effect on both mitochondrial respiration and glycolysis in GBM cells. These effects would lead to decreased tumor size and rate of growth, representing a potential treatment to control the spread of GBM.

Keywords:  Glioblastoma multiforme; Glycolysis; Mitochondria; Oxidative phosphorylation; Progesterone treatment

DOI:  https://doi.org/10.1007/s12035-021-02382-1
Clin Epigenetics. 2021 Apr 12. 13(1): 77

Integrative study of EZH2 mutational status, copy number, protein expression and H3K27 trimethylation in AML/MDS patients.

Julia Stomper, Ruth Meier, Tobias Ma, Dietmar Pfeifer, Gabriele Ihorst, Nadja Blagitko-Dorfs, Gabriele Greve, Dennis Zimmer, Uwe Platzbecker, Anne Hagemeijer, Annette Schmitt-Gräff, Michael Lübbert.

  BACKGROUND: Mutations in the EZH2 gene are recurrently found in patients with myeloid neoplasms and are associated with a poor prognosis. We aimed to characterize genetic and epigenetic alterations of EZH2 in 58 patients (51 with acute myeloid leukemia and 7 with myelodysplastic or myeloproliferative neoplasms) by integrating data on EZH2 mutational status, co-occurring mutations, and EZH2 copy number status with EZH2 protein expression, histone H3K27 trimethylation, and EZH2 promoter methylation.RESULTS: EZH2 was mutated in 6/51 acute myeloid leukemia patients (12%) and 7/7 patients with other myeloid neoplasms. EZH2 mutations were not overrepresented in patients with chromosome 7q deletions or losses. In acute myeloid leukemia patients, EZH2 mutations frequently co-occurred with CEBPA (67%), ASXL1 (50%), TET2 and RAD21 mutations (33% each). In EZH2-mutated patients with myelodysplastic or myeloproliferative neoplasms, the most common co-mutations were in ASXL1 (100%), NRAS, RUNX1, and STAG2 (29% each). EZH2 mutations were associated with a significant decrease in EZH2 expression (p = 0.0002), which was similar in patients with chromosome 7 aberrations and patients with intact chromosome 7. An association between EZH2 protein expression and H3K27 trimethylation was observed in EZH2-unmutated patients (R2 = 0.2, p = 0.01). The monoallelic state of EZH2 was not associated with EZH2 promoter hypermethylation. In multivariable analyses, EZH2 mutations were associated with a trend towards an increased risk of death (hazard ratio 2.51 [95% confidence interval 0.87-7.25], p = 0.09); similarly, low EZH2 expression was associated with elevated risk (hazard ratio 2.54 [95% confidence interval 1.07-6.04], p = 0.04).
CONCLUSIONS: Perturbations of EZH2 activity in AML/MDS occur on different, genetic and non-genetic levels. Both low EZH2 protein expression and, by trend, EZH2 gene mutations predicted inferior overall survival of AML patients receiving standard chemotherapy.

Keywords:  Acute myeloid leukemia; EZH2; H3K27 trimethylation; Mutations; Promoter methylation; Protein expression; Survival

DOI:  https://doi.org/10.1186/s13148-021-01052-2
Cell Stem Cell. 2021 Apr 07. pii: S1934-5909(21)00123-5. [Epub ahead of print]

Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging.

Kira Young, Elizabeth Eudy, Rebecca Bell, Matthew A Loberg, Tim Stearns, Devyani Sharma, Lars Velten, Simon Haas, Marie-Dominique Filippi, Jennifer J Trowbridge.

  Decline in hematopoietic stem cell (HSC) function with age underlies limited health span of our blood and immune systems. In order to preserve health into older age, it is necessary to understand the nature and timing of initiating events that cause HSC aging. By performing a cross-sectional study in mice, we discover that hallmarks of aging in HSCs and hematopoiesis begin to accumulate by middle age and that the bone marrow (BM) microenvironment at middle age induces and is indispensable for hematopoietic aging. Using unbiased approaches, we find that decreased levels of the longevity-associated molecule IGF1 in the local middle-aged BM microenvironment are a factor causing HSC aging. Direct stimulation of middle-aged HSCs with IGF1 rescues molecular and functional hallmarks of aging, including restored mitochondrial activity. Thus, although decline in IGF1 supports longevity, our work indicates that this also compromises HSC function and limits hematopoietic health span.

Keywords:  IGF1; aging; healthspan; hematopoiesis; hematopoietic stem cell; lineage bias; metabolism; microenvironment; middle age; niche

DOI:  https://doi.org/10.1016/j.stem.2021.03.017