bims-almceb 2022-08-07 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022‒08‒07
seven papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia.
An Emergent Role for Mitochondrial Bioenergetics in the Action of Snake Venom Toxins on Cancer Cells.
Suppressing crucial oncogenes of leukemia initiator cells by major royal jelly protein 2 for mediating apoptosis in myeloid and lymphoid leukemia cells.
A novel strategy to fuel cancer immunotherapy: targeting glucose metabolism to remodel the tumor microenvironment.
Acute myeloid leukemia fusion genes can be found in CD33-negative cells.
Early Growth Response Factor 1 in Aging Hematopoietic Stem Cells and Leukemia.
Turning the clock forward: Inflammation accelerates the aging of hematopoietic stem cells.

Cell Death Dis. 2022 Aug 02. 13(8): 671

BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia.

Mengjun Zhong, Rili Gao, Ruocong Zhao, Youxue Huang, Cunte Chen, Kehan Li, Xibao Yu, Dingrui Nie, Zheng Chen, Xin Liu, Zhuandi Liu, Shaohua Chen, Yuhong Lu, Zhi Yu, Liang Wang, Peng Li, Chengwu Zeng, Yangqiu Li.

Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1/Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1/PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy.

DOI: https://doi.org/10.1038/s41419-022-05123-x
Front Oncol. 2022 ;12 938749

An Emergent Role for Mitochondrial Bioenergetics in the Action of Snake Venom Toxins on Cancer Cells.

Félix A Urra, Dan E Vivas-Ruiz, Eladio Flores Sanchez, Ramiro Araya-Maturana.

  Beyond the role of mitochondria in apoptosis initiation/execution, some mitochondrial adaptations support the metastasis and chemoresistance of cancer cells. This highlights mitochondria as a promising target for new anticancer strategies. Emergent evidence suggests that some snake venom toxins, both proteins with enzymatic and non-enzymatic activities, act on the mitochondrial metabolism of cancer cells, exhibiting unique and novel mechanisms that are not yet fully understood. Currently, six toxin classes (L-amino acid oxidases, thrombin-like enzymes, secreted phospholipases A2, three-finger toxins, cysteine-rich secreted proteins, and snake C-type lectin) that alter the mitochondrial bioenergetics have been described. These toxins act through Complex IV activity inhibition, OXPHOS uncoupling, ROS-mediated permeabilization of inner mitochondrial membrane (IMM), IMM reorganization by cardiolipin interaction, and mitochondrial fragmentation with selective migrastatic and cytotoxic effects on cancer cells. Notably, selective internalization and direct action of snake venom toxins on tumor mitochondria can be mediated by cell surface proteins overexpressed in cancer cells (e.g. nucleolin and heparan sulfate proteoglycans) or facilitated by the elevated Δψm of cancer cells compared to that non-tumor cells. In this latter case, selective mitochondrial accumulation, in a Δψm-dependent manner, of compounds linked to cationic snake peptides may be explored as a new anti-cancer drug delivery system. This review analyzes the effect of snake venom toxins on mitochondrial bioenergetics of cancer cells, whose mechanisms of action may offer the opportunity to develop new anticancer drugs based on toxin scaffolds.

Keywords:  OXPHOS (oxidative phosphorylation); anticancer compounds; cardiolipin; electron transport chain; migrastatics; mitochondrial dysfunction; snake venom

DOI:  https://doi.org/10.3389/fonc.2022.938749
Food Funct. 2022 Aug 05.

Suppressing crucial oncogenes of leukemia initiator cells by major royal jelly protein 2 for mediating apoptosis in myeloid and lymphoid leukemia cells.

Marwa M Abu-Serie, Noha H Habashy.

Relapse of leukemia and drug resistance are still the major obstacles to therapy due to leukemia-initiating stem/progenitor cells (LICs); thus, targeting them using safe compounds is crucial. Here, we evaluated the anti-leukemic effect of royal jelly (RJ) components, which had a higher safe concentration (EC100 values) than the chemotherapeutic drug doxorubicin (DOX). The RJ-protein fraction 50 (PF50, precipitated at 40-50% ammonium sulfate saturation) and its constituents, major RJ protein (MRJP) 2 and its isoform X1, exhibited the highest growth inhibitory effect against myeloid NFS-60 and lymphoid Jurkat cell lines. MRJP2 has a nanosize, which may be the reason for its higher anti-leukemic activity than its isoform. These RJ proteins, particularly MRJP2, suppressed LIC-associated oncogenes (GATA2 and Evi-1) and eliminated CD34+ LICs, in contrast to the low anti-LIC efficacy of DOX. MRJP2 demonstrated higher apoptotic activity than its isoform by upregulating p53 and p21-mediated cell cycle arrest. This study also reported the potent inhibitory effect of RJ-proteins on matrix metallopeptidase 10 (metastatic marker) and histone deacetylase 8 (mediates LIC survival) activities. Thus, MRJP2 can be considered a promising novel therapeutic agent for both myeloid and lymphoid leukemia.

DOI: https://doi.org/10.1039/d2fo00999d
Front Oncol. 2022 ;12 931104

A novel strategy to fuel cancer immunotherapy: targeting glucose metabolism to remodel the tumor microenvironment.

Xu Liu, Yujie Zhao, Xi Wu, Zhihui Liu, Xiaowei Liu.

  The promising results of immunotherapy in tumors have changed the current treatment modality for cancer. However, the remarkable responses are limited to a minority of patients, which is due to immune suppression in the tumor microenvironment (TME). These include the pre-exists of suppressive immune cells, physical barriers to immune infiltration, antigen and antigen presentation deficiency, and expression of inhibitory immune checkpoint molecules. Recently, increasing evidence reveal that tumor metabolism, especially abnormal glucose metabolism of tumors, plays an essential role in tumor immune escape and is a potential target to combine with immunotherapy. By glucose uptake, tumor cells alter their metabolism to facilitate unregulated cellular proliferation and survival and regulate the expression of inhibitory immune checkpoint molecules. Meanwhile, glucose metabolism also regulates the activation, differentiation, and functions of immunocytes. In addition, tumor mainly utilizes glycolysis for energy generation and cellular proliferation, which cause the TME to deplete nutrients for infiltrating immune cells such as T cells and produce immunosuppressive metabolites. Thus, therapeutics that target glucose metabolism, such as inhibiting glycolytic activity, alleviating hypoxia, and targeting lactate, have shown promise as combination therapies for different types of cancer. In this review, we summarized the functions of glucose metabolism in the tumor cells, immune cells, and tumor microenvironment, as well as strategies to target glucose metabolism in combination with immune checkpoint blockade for tumor therapy.

Keywords:  aerobic glycolysis; glucose metabolism; immune checkpoint inhibitors; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.931104
Int J Lab Hematol. 2022 Aug 02.

Acute myeloid leukemia fusion genes can be found in CD33-negative cells.

Yuan Chen, Qian Liu, Haiyan Xing, Qing Rao, Min Wang, Yingchang Mi, Hui Wei, Jianxiang Wang.

  INTRODUCTION: Targeted therapies and immunotherapies are emerging strategies for the treatment of leukemia. CD33 is a common and important therapeutic target for cellular immunotherapy or antibody immunotherapy. Drugs on targeting CD33 are also emerging. However, acute myeloid leukemia (AML) relapse still occurs after treatment with targeted CD33, for which the mechanism is unknown.METHODS: We used fluorescence in situ hybridization and real-time polymerase chain reaction to detect the expression of fusion genes in different populations of cells from AML patients.
RESULT: Fusion gene can be express in CD33 negative cell proportions in newly diagnosed and relapsed AML patients.
CONCLUSION: There are fusion genes in CD33-negative cells that are might not be cleared by CD33 targeting therapy. And this might be the source of relapse.

Keywords:  AML; CD33; target therapy

DOI:  https://doi.org/10.1111/ijlh.13942
Front Cell Dev Biol. 2022 ;10 925761

Early Growth Response Factor 1 in Aging Hematopoietic Stem Cells and Leukemia.

Rohan Kulkarni.

  Aging is associated with various hematological disorders and a higher risk of myeloproliferative disorders. An aged hematopoietic system can be characterized by decreased immune function and increased myeloid cell production. Hematopoietic stem cells (HSCs) regulate the production of blood cells throughout life. The self-renewal and regenerative potential of HSCs determine the quality and quantity of the peripheral blood cells. External signals from the microenvironment under different conditions determine the fate of the HSCs to proliferate, self-renew, differentiate, or remain quiescent. HSCs respond impromptu to a vast array of extracellular signaling cascades such as cytokines, growth factors, or nutrients, which are crucial in the regulation of HSCs. Early growth response factor 1 (EGR1) is one of the key transcription factors controlling HSC proliferation and their localization in the bone marrow (BM) niche. Downregulation of Egr1 activates and recruits HSCs for their proliferation and differentiation to produce mature blood cells. Increased expression of Egr1 is implicated in immuno-aging of HSCs. However, dysregulation of Egr1 is associated with hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML). Here, we summarize the current understanding of the role of EGR1 in the regulation of HSC functionality and the manifestation of leukemia. We also discuss the alternative strategies to rejuvenate the aged HSCs by targeting EGR1 in different settings.

Keywords:  HSC activation; HSC rejuvenation; aged HSCs; early growth response 1 (EGR1); hematopoitic stem cells; leukemia

DOI:  https://doi.org/10.3389/fcell.2022.925761
Cell Stem Cell. 2022 Aug 04. pii: S1934-5909(22)00297-1. [Epub ahead of print]29(8): 1156-1158

Turning the clock forward: Inflammation accelerates the aging of hematopoietic stem cells.

Sarah S Burns, Reuben Kapur.

In the current issue of Cell Stem Cell, Bogeska et al. demonstrate that repeated exposures to inflammation cause indelible and specific functional compromise and accelerated aging of long-term hematopoietic stem cells (LT-HSCs). This study proposes the notion that the cumulative inflammatory events over the course of an organism's lifespan may irreversibly damage LT-HSCs.

DOI: https://doi.org/10.1016/j.stem.2022.07.002