bims-almceb 2021-03-28 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–03–28
thirteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis.
OGP46 Induces Differentiation of Acute Myeloid Leukemia Cells via Different Optimal Signaling Pathways.
Mitochondrial C3a Receptor Activation in Oxidatively Stressed Epithelial Cells Reduces Mitochondrial Respiration and Metabolism.
DNA damage response protein CHK2 regulates metabolism in liver cancer.
Emerging role of autophagy in anti-tumor immunity: Implications for the modulation of immunotherapy resistance.
Emerging agents and regimens for AML.
Chemotherapy regimens induce inhibitory immune checkpoint protein expression on stem-like and senescent-like oesophageal adenocarcinoma cells.
A novel target for combination immunotherapy in pancreatic cancer: IL-1β mediates immunosuppression in the tumour microenvironment.
Impact of TCM on Tumor-Infiltrating Myeloid Precursors in the Tumor Microenvironment.
Prognostic Relevance of Expression of EMP1, CASP1, and NLRP3 Genes in Pediatric B-Lineage Acute Lymphoblastic Leukemia.
Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.
Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma.
CDK9 Inhibitor Induces the Apoptosis of B-Cell Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolytic Metabolism.

Cell Metab. 2021 Mar 23. pii: S1550-4131(21)00110-8. [Epub ahead of print]

Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis.

Yi-Ping Wang, Azeem Sharda, Shuang-Nian Xu, Nick van Gastel, Cheuk Him Man, Una Choi, Wei Zhong Leong, Xi Li, David T Scadden.

  Mitochondria have an independent genome (mtDNA) and protein synthesis machinery that coordinately activate for mitochondrial generation. Here, we report that the Krebs cycle intermediate fumarate links metabolism to mitobiogenesis through binding to malic enzyme 2 (ME2). Mechanistically, fumarate binds ME2 with two complementary consequences. First, promoting the formation of ME2 dimers, which activate deoxyuridine 5'-triphosphate nucleotidohydrolase (DUT). DUT fosters thymidine generation and an increase of mtDNA. Second, fumarate-induced ME2 dimers abrogate ME2 monomer binding to mitochondrial ribosome protein L45, freeing it for mitoribosome assembly and mtDNA-encoded protein production. Methylation of the ME2-fumarate binding site by protein arginine methyltransferase-1 inhibits fumarate signaling to constrain mitobiogenesis. Notably, acute myeloid leukemia is highly dependent on mitochondrial function and is sensitive to targeting of the fumarate-ME2 axis. Therefore, mitobiogenesis can be manipulated in normal and malignant cells through ME2, an unanticipated governor of mitochondrial biomass production that senses nutrient availability through fumarate.

Keywords:  acute myeloid leukemia; arginine methylation; deoxyuridine 5′-triphosphate nucleotidohydrolase; fumarate; malic enzyme 2; mitobiogenesis; mitochondrial ribosome; mitochondrial ribosome protein L45; protein arginine methyltransferase 1

DOI:  https://doi.org/10.1016/j.cmet.2021.03.003
Front Cell Dev Biol. 2021 ;9 652972

OGP46 Induces Differentiation of Acute Myeloid Leukemia Cells via Different Optimal Signaling Pathways.

Min Zhao, Jiangyun Wang, Mei Qu, Yao Zhao, Haihua Wang, Yu Ke, Ying Liu, Zi-Ning Lei, Hong-Min Liu, Zhenbo Hu, Liuya Wei, Zhe-Sheng Chen.

  Acute myelogenous leukemia (AML) is characterized by blockage of cell differentiation leading to the accumulation of immature cells, which is the most prevalent form of acute leukemia in adults. It is well known that all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are the preferred drugs for acute promyelocytic leukemia (APL). However, they can lead to irreversible resistance which may be responsible for clinical failure after complete remission (CR). Moreover, the differentiation therapy of ATRA-based treatment has not been effective against AML with t(8;21) translocation. Here we aimed to identify the differentiation effect of OGP46 on AML cell lines (HL-60, NB4, and Kasumi-1) and explore its possible mechanisms. We found that OGP46 has significant inhibitory activity against these cells by triggering cell differentiation with cell-cycle exit at G1/G0 and inhibited the colony-formation capacity of the AML cells. It was shown that OGP46 induced the differentiation of NB4 cells via the transcriptional misregulation in cancer signaling pathway by PML-RARα depletion, while it was attributed to the hematopoietic cell lineage and phagosome pathway in Kasumi-1 cells, which are all critical pathways in cell differentiation. These results highlight that OGP46 is an active agent not only in the APL cell line NB4 but also in AML-M2 cell lines, especially Kasumi-1 with t(8;21) translocation. Therefore, OGP46 may be a potential compound for surmounting the differentiation blockage in AML.

Keywords:  AML cells with t(8;21) translocation; PML-RARα depletion; acute myeloid leukemia; acute promyelocytic leukemia; differentiation therapy

DOI:  https://doi.org/10.3389/fcell.2021.652972
Front Immunol. 2021 ;12 628062

Mitochondrial C3a Receptor Activation in Oxidatively Stressed Epithelial Cells Reduces Mitochondrial Respiration and Metabolism.

Masaaki Ishii, Gyda Beeson, Craig Beeson, Bärbel Rohrer.

  Complement component 3 fragment C3a is an anaphylatoxin involved in promoting cellular responses important in immune response and host defense. Its receptor (C3a receptor, C3aR) is distributed on the plasma membrane; however, lysosomal localization in immune cells has been reported. Oxidative stress increases intracellular reactive oxygen species (ROS), and ROS activate complement signaling in immune cells and metabolic reprogramming. Here we tested oxidative stress and intracellular complement in mitochondrial dysfunction in RPE cells using high resolution live-cell imaging, and metabolism analysis in isolated mitochondria using Seahorse technology. While C3aR levels were unaffected by oxidative stress, its cell membrane levels decreased and mitochondrial (mt) localization increased. Trafficking was dependent on endocytosis, utilizing endosomal-to-mitochondrial cargo transfer. H2O2-treatment also increased C3a-mtC3aR co-localization dose-dependently. In isolated mitochondria from H2O2-treated cells C3a increased mitochondrial Ca2+ uptake, that could be inhibited by C3aR antagonism (SB290157), mitochondrial Ca2+ uniporter blocker (Ru360), and Gαi-protein inhibition (pertussis toxin, PTX); and inhibited mitochondrial repiration in an SB290157- and PTX-dependent manner. Specifically, mtC3aR activation inhibited state III ADP-driven respiration and maximal respiratory capacity. Mitochondria from control cells did not respond to C3a. Furthermore, transmitochondrial cybrid ARPE-19 cells harboring J haplogroup mitochondria that confer risk for age-related macular degeneration, showed high levels of mtC3aR and reduced ATP production upon C3a stimulation. Our findings suggest that oxidative stress increases mtC3aR, leading to altered mitochondrial calcium uptake and ATP production. These studies will have important implication in our understanding on the balance of extra- and intracellular complement signaling in controlling cellular health and dysfunction.

Keywords:  calcium imaging; complement C3a receptor; endosomal targeting; mitochondria; oxidative phosphorylation; translocation

DOI:  https://doi.org/10.3389/fimmu.2021.628062
Cancer Res. 2021 Mar 24. pii: canres.3134.2020. [Epub ahead of print]

DNA damage response protein CHK2 regulates metabolism in liver cancer.

Matteo Lulli, Laura Del Coco, Tommaso Mello, Caecilia Sukowati, Stefania Madiai, Laura Gragnani, Paolo Forte, Francesco Paolo Fanizzi, Antonio Mazzocca, Krista Rombouts, Andrea Galli, Vinicio Carloni.

Defective mitosis with chromosome missegregation can have a dramatic effect on genome integrity by causing DNA damage, activation of the DNA damage response (DDR), and chromosomal instability. Although this is an energy-dependent process, mechanisms linking DDR to cellular metabolism are unknown. Here we show that checkpoint kinase 2 (CHK2), a central effector of DDR, regulates cellular energy production by affecting glycolysis and mitochondrial functions. Patients with hepatocellular carcinoma (HCC) had increased CHK2 mRNA in blood, which was associated with elevated tricarboxylic acid cycle (TCA) metabolites. CHK2 controlled expression of succinate dehydrogenase (SDH) and intervened with mitochondrial functions. DNA damage and CHK2 promoted SDH activity marked by increased succinate oxidation through the TCA cycle; this was confirmed in a transgenic model of HCC with elevated DNA damage. Mitochondrial analysis identified CHK2-controlled expression of SDH as key in sustaining reactive oxygen species production. Cells with DNA damage and elevated CHK2 relied significantly on glycolysis for ATP production due to dysfunctional mitochondria, which was abolished by CHK2 knockdown. This represents a vulnerability created by the DNA damage response that could be exploited for development of new therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-3134
Drug Resist Updat. 2021 Feb 16. pii: S1368-7646(21)00010-8. [Epub ahead of print]56 100752

Emerging role of autophagy in anti-tumor immunity: Implications for the modulation of immunotherapy resistance.

Ting Jiang, Xisha Chen, Xingcong Ren, Jin-Ming Yang, Yan Cheng.

  Immunotherapies such as CAR-T cell transfer and antibody-targeted therapy have produced promising clinical outcomes in patients with advanced and metastatic cancer that are resistant to conventional therapies. However, with increasing use of cancer immunotherapy in clinical treatment, multiple therapy-resistance mechanisms have gradually emerged. The tumor microenvironment (TME), an integral component of cancer, can significantly influence the therapeutic response. Thus, it is worth exploring the potential of TME in modulating therapy resistance, in the hope to devise novel strategies to reinforcing anti-cancer treatments such as immunotherapy. As a crucial recycling process in the complex TME, the role of autophagy in tumor immunity has been increasingly appreciated. Firstly, autophagy in tumor cells can affect their immune response through modulating MHC-I-antigen complexes, thus modulating immunogenic tumor cell death, changing functions of immune cells via secretory autophagy, reducing the NK- and CTL-mediated cell lysis and degradation of immune checkpoint proteins. Secondly, autophagy is critical for the differentiation, maturation and survival of immune cells in the TME and can significantly affect the immune function of these cells, thereby regulating the anti-tumor immune response. Thirdly, alteration of autophagic activity in stromal cells, especially in fibroblasts, can reconstruct the three-dimensional stromal environment and metabolic reprogramming in the TME. A number of studies have demonstrated that optimal induction or inhibition of autophagy may lead to effective therapeutic regimens when combined with immunotherapy. This review discusses the important roles of autophagy in tumor cells, immune cells and stromal cells in the context of tumor immunity, and the potential of combining the autophagy-based therapy with immunotherapy as novel therapeutic approaches against cancer.

Keywords:  Autophagy; Immunotherapy; Resistance; Tumor immunity; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.drup.2021.100752
J Hematol Oncol. 2021 Mar 23. 14(1): 49

Emerging agents and regimens for AML.

Hongtao Liu.

  Until recently, acute myeloid leukemia (AML) patients used to have limited treatment options, depending solely on cytarabine + anthracycline (7 + 3) intensive chemotherapy and hypomethylating agents. Allogeneic stem cell transplantation (Allo-SCT) played an important role to improve the survival of eligible AML patients in the past several decades. The exploration of the genomic and molecular landscape of AML, identification of mutations associated with the pathogenesis of AML, and the understanding of the mechanisms of resistance to treatment from excellent translational research helped to expand the treatment options of AML quickly in the past few years, resulting in noteworthy breakthroughs and FDA approvals of new therapeutic treatments in AML patients. Targeted therapies and combinations of different classes of therapeutic agents to overcome treatment resistance further expanded the treatment options and improved survival. Immunotherapy, including antibody-based treatment, inhibition of immune negative regulators, and possible CAR T cells might further expand the therapeutic armamentarium for AML. This review is intended to summarize the recent developments in the treatment of AML.

Keywords:  AML; Novel treatment; Targeted therapy

DOI:  https://doi.org/10.1186/s13045-021-01062-w
Transl Oncol. 2021 Mar 22. pii: S1936-5233(21)00054-1. [Epub ahead of print]14(6): 101062

Chemotherapy regimens induce inhibitory immune checkpoint protein expression on stem-like and senescent-like oesophageal adenocarcinoma cells.

Maria Davern, Noel E Donlon, Andrew Sheppard, Fiona O' Connell, Conall Hayes, Anshul Bhardwaj, Emma Foley, Dermot O' Toole, Niamh Lynam-Lennon, Narayanasamy Ravi, John V Reynolds, Stephen G Maher, Joanne Lysaght.

  Use of immune checkpoint inhibitors (ICIs) with chemotherapy to enhance responses in oesophageal adenocarcinoma (OAC) is an attractive approach. We identified subpopulations of OAC cells expressing inhibitory immune checkpoint (IC) ligands (PD-L1, PD-L2 and CD160) and receptors (PD-1, TIGIT, TIM-3, LAG-3 and A2aR) in vitro and in ex vivo biopsies. Combination chemotherapy regimens FLOT and CROSS promote a more immune-resistant phenotype through upregulation of IC ligands and receptors on OAC cells in vitro. Importantly, this study investigated if OAC cells, enriched for ICs exhibited a more stem-like and senescent-like phentoype. FLOT preferentially upregulates PD-L1 on a stem-like OAC cell phenotype, defined by ALDH activity. Expression of senescence-associated β-galactosidase is induced in a subpopulation of OAC cells following FLOT and CROSS chemotherapy treatment, along with enhanced expression of TIM-3 and A2aR ICs. Blockade of PD-1 signalling in OAC cells induced apoptosis and enhanced FLOT and CROSS chemotherapy toxicity in vitro. Upregulation of ICs on OAC cells following chemotherapy may represent potential mechanisms of chemo-immune resistance. Combination ICIs may be required to enhance the efficacy of chemotherapy and immunotherapy in OAC patients.

Keywords:  Chemotherapy; Immune checkpoints; Oesophageal adenocarcinoma; Senescence; Stem-like

DOI:  https://doi.org/10.1016/j.tranon.2021.101062
Br J Cancer. 2021 Mar 23.

A novel target for combination immunotherapy in pancreatic cancer: IL-1β mediates immunosuppression in the tumour microenvironment.

Rafael Winograd, Diane M Simeone, Dafna Bar-Sagi.

Immune checkpoint blockade (ICB) has demonstrated efficacy in multiple cancers, offering the potential of long-term disease control not achievable with cytotoxic or targeted therapies. However, the field has not yet achieved the crucial next steps - the expansion of the response rate and achievement of clinical efficacy in so-called "cold tumours". Mechanistic studies of tumour-type specific immunosuppressive pathways can reveal underlying biological hurdles to immunotherapy and offer new therapeutic insights. Our finding that tumour-derived IL-1β mediates immunosuppression in pancreatic cancer has precipitated a new clinical trial.

DOI: https://doi.org/10.1038/s41416-021-01303-2
Front Cell Dev Biol. 2021 ;9 635122

Impact of TCM on Tumor-Infiltrating Myeloid Precursors in the Tumor Microenvironment.

Jinlong Liu, Yuchen Wang, Zhidong Qiu, Guangfu Lv, Xiaowei Huang, He Lin, Zhe Lin, Peng Qu.

  The tumor microenvironment (TME) is composed of tumor cells, blood/lymphatic vessels, the tumor stroma, and tumor-infiltrating myeloid precursors (TIMPs) as a sophisticated pathological system to provide the survival environment for tumor cells and facilitate tumor metastasis. In TME, TIMPs, mainly including tumor-associated macrophage (TAM), tumor-associated dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs), play important roles in repressing the antitumor activity of T cell or other immune cells. Therefore, targeting those cells would be one novel efficient method to retard cancer progression. Numerous studies have shown that traditional Chinese medicine (TCM) has made extensive research in tumor immunotherapy. In the review, we demonstrate that Chinese herbal medicine (CHM) and its components induce tumor cell apoptosis, directly inhibiting tumor growth and invasion. Further, we discuss that TCM regulates TME to promote effective antitumor immune response, downregulates the numbers and function of TAMs/MDSCs, and enhances the antigen presentation ability of mature DCs. We also review the therapeutic effects of TCM herbs and their ingredients on TIMPs in TME and systemically analyze the regulatory mechanisms of TCM on those cells to have a deeper understanding of TCM in tumor immunotherapy. Those investigations on TCM may provide novel ideas for cancer treatment.

Keywords:  cancer immunotherapy; regulatory mechanism; traditional Chinese medicine; tumor microenvironment; tumor-infiltrating myeloid precursors

DOI:  https://doi.org/10.3389/fcell.2021.635122
Front Oncol. 2021 ;11 606370

Prognostic Relevance of Expression of EMP1, CASP1, and NLRP3 Genes in Pediatric B-Lineage Acute Lymphoblastic Leukemia.

Jay Singh, Sarita Kumari, Mohit Arora, Deepak Verma, Jayanth Kumar Palanichamy, Rajive Kumar, Gunjan Sharma, Sameer Bakhshi, Deepam Pushpam, M Shadab Ali, Amar Ranjan, Pranay Tanwar, Shyam S Chauhan, Archna Singh, Anita Chopra.

  Glucocorticoid (GC), such as prednisolone, is an essential component of multidrug chemotherapy regimen for pediatric acute lymphoblastic leukemia (ALL). Resistance to GC in leukemia cells is associated with disease progression and poor prognosis. Despite the extensive use of GC for many years, molecular mechanisms underlying its resistance in ALL have not been fully uncovered. Recent studies have shown a potential role of EMP1, CASP1, and NLRP3 genes in prednisolone response. In this study on 148 pediatric B-ALL patients, we studied these three genes to assess their association with prednisolone response measured by day 8 blast count after 7 days of induction therapy with prednisolone. Intriguingly, ALL samples exhibited higher expression of EMP1 along with a low expression of CASP1 and NLRP3 compared to disease free normal bone marrow collected from patients with solid tumors. Among the three analyzed genes, only EMP1 was found to be overexpressed in prednisolone poor responders (p=0.015). Further, a comparison of gene expression between cytogenetic subtypes revealed higher expression of EMP1 in BCR-ABL subtype. Expression of EMP1 in multiple gene expression datasets was used for gene set enrichment analysis, which revealed TNF-α, IL-2-STAT5 signaling, inflammatory responses and hypoxia as the major positively associated pathways and E2F targets as negatively associated pathways. Interestingly, the clinical remission rate was higher in CASP1 high patients (p=0.048). In univariate survival analysis, higher EMP1 expression was associated with poor prognostic measures while higher expression of NLRP3 and CASP1 was associated with better prognostic measures in our data. Further, multivariate analysis revealed an independent association of high CASP1 and NLRP3 with a better prognosis. This study strengthens the available evidence that mRNA expression of EMP1, CASP1, and NLRP3 may serve as potential biomarkers for risk stratification of pediatric B-ALL patients.

Keywords:  B-ALL; CASP1; EMP1; NLRP3; leukemia; prednisolone resistance

DOI:  https://doi.org/10.3389/fonc.2021.606370
J Exp Med. 2021 May 03. pii: e20200924. [Epub ahead of print]218(5):

Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.

Lucille Stuani, Marie Sabatier, Estelle Saland, Guillaume Cognet, Nathalie Poupin, Claudie Bosc, Florence A Castelli, Lara Gales, Evgenia Turtoi, Camille Montersino, Thomas Farge, Emeline Boet, Nicolas Broin, Clément Larrue, Natalia Baran, Madi Y Cissé, Marc Conti, Sylvain Loric, Tony Kaoma, Alexis Hucteau, Aliki Zavoriti, Ambrine Sahal, Pierre-Luc Mouchel, Mathilde Gotanègre, Cédric Cassan, Laurent Fernando, Feng Wang, Mohsen Hosseini, Emeline Chu-Van, Laurent Le Cam, Martin Carroll, Mary A Selak, Norbert Vey, Rémy Castellano, François Fenaille, Andrei Turtoi, Guillaume Cazals, Pierre Bories, Yves Gibon, Brandon Nicolay, Sébastien Ronseaux, Joseph R Marszalek, Koichi Takahashi, Courtney D DiNardo, Marina Konopleva, Véra Pancaldi, Yves Collette, Floriant Bellvert, Fabien Jourdan, Laetitia K Linares, Christian Récher, Jean-Charles Portais, Jean-Emmanuel Sarry.

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

DOI: https://doi.org/10.1084/jem.20200924
Proc Natl Acad Sci U S A. 2021 Mar 30. pii: e2009620118. [Epub ahead of print]118(13):

Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma.

Krista M Dalton, Timothy L Lochmann, Konstantinos V Floros, Marissa L Calbert, Richard Kurupi, Giovanna T Stein, Joseph McClanaghan, Ellen Murchie, Regina K Egan, Patricia Greninger, Mikhail Dozmorov, Sivapriya Ramamoorthy, Madhavi Puchalapalli, Bin Hu, Lisa Shock, Jennifer Koblinski, John Glod, Sosipatros A Boikos, Cyril H Benes, Anthony C Faber.

  MYCN-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. The understanding that both compensatory pathways and intrinsic redundancy in cell systems exists implies that the use of combination therapies for effective and durable responses is necessary. Additionally, the most effective targeted therapies exploit an "Achilles' heel" and are tailored to the genetics of the cancer under study. We performed an unbiased screen on select metabolic targeted therapy combinations and correlated sensitivity with over 20 subsets of cancer. We found that MYCN-amplified neuroblastoma is hypersensitive to the combination of an inhibitor of the lactate transporter MCT1, AZD3965, and complex I of the mitochondrion, phenformin. Our data demonstrate that MCT4 is highly correlated with resistance to the combination in the screen and lowly expressed in MYCN-amplified neuroblastoma. Low MCT4 combines with high expression of the MCT2 and MCT1 chaperone CD147 in MYCN-amplified neuroblastoma, altogether conferring sensitivity to the AZD3965 and phenformin combination. The result is simultaneous disruption of glycolysis and oxidative phosphorylation, resulting in dramatic disruption of adenosine triphosphate (ATP) production, endoplasmic reticulum stress, and cell death. In mouse models of MYCN-amplified neuroblastoma, the combination was tolerable at concentrations where it shrank tumors and did not increase white-blood-cell toxicity compared to single drugs. Therefore, we demonstrate that a metabolic combination screen can identify vulnerabilities in subsets of cancer and put forth a metabolic combination therapy tailored for MYCN-amplified neuroblastoma that demonstrates efficacy and tolerability in vivo.

Keywords:  MYCN; apoptosis; lactate; metabolomics; neuroblastoma

DOI:  https://doi.org/10.1073/pnas.2009620118
Front Cell Dev Biol. 2021 ;9 641271

CDK9 Inhibitor Induces the Apoptosis of B-Cell Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolytic Metabolism.

Wen-Li Huang, Tuersunayi Abudureheman, Jing Xia, Lei Chu, Hang Zhou, Wei-Wei Zheng, Neng Zhou, Rong-Yi Shi, Ming-Hao Li, Jian-Min Zhu, Kai Qing, Chao Ji, Kai-Wei Liang, Sa Guo, Gang Yin, Cai-Wen Duan.

  B-cell acute lymphocytic leukemia (B-ALL), a common blood cancer in children, leads to high mortality. Cyclin-dependent kinase 9 inhibitor (CDK9i) effectively attenuates acute myeloid leukemia and chronic lymphoblastic leukemia by inducing apoptosis and inhibiting cell proliferation. However, the effect of CDK9i on B-ALL cells and the underlying mechanisms remain unclear. In this study, we showed that CDK9i induced the apoptosis of B-ALL cells in vitro by activating the apoptotic pathways. In addition, CDK9i restrained the glycolytic metabolism of B-ALL cells, and CDK9i-induced apoptosis was enhanced by co-treatment with glycolysis inhibitors. Furthermore, CDK9i restained the glycolysis of B-ALL cell lines by markedly downregulating the expression of glucose transporter type 1 (GLUT1) and the key rate-limiting enzymes of glycolysis, such as hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Moreover, cell apoptosis was rescued in B-ALL cells with over-expressed c-Myc after treatment with CDK9i, which is involved in the enhancement of glycolytic metabolism. In summary, our findings suggest that CDK9 inhibitors induce the apoptosis of B-ALL cells by inhibiting c-Myc-mediated glycolytic metabolism, thus providing a new strategy for the treatment of B-ALL.

Keywords:  B-cell acute lymphocytic leukemia; CDK9 inhibitors; c-Myc; cell apoptosis; glycolysis

DOI:  https://doi.org/10.3389/fcell.2021.641271