bims-almceb 2022-12-04 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022‒12‒04
nine papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

Identification of natural products and FDA-approved drugs for targeting cancer stem cell (CSC) propagation.
Editorial: Linking cellular metabolism to hematological malignancies.
Resistance to immune checkpoint inhibitors and the tumor microenvironment.
Associating immunotherapy and targeted therapies: facts and hopes.
Repurposing immunosuppressants for antileukemia therapy.
Immunosuppressive Extracellular Vesicles in CLL.
A Novel Prognostic Model for Acute Myeloid Leukemia Based on Gene Set Variation Analysis.
Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia.
The present and future of measurable residual disease testing in acute myeloid leukemia.

Aging (Albany NY). 2022 Dec 01. 14

Identification of natural products and FDA-approved drugs for targeting cancer stem cell (CSC) propagation.

Gloria Bonuccelli, Federica Sotgia, Michael P Lisanti.

  Here, we report the identification of key compounds that effectively inhibit the anchorage-independent growth and propagation of cancer stem cells (CSCs), as determined via screening using MCF7 cells, a human breast adenocarcinoma cell line. More specifically, we employed the mammosphere assay as an experimental format, which involves the generation of 3D spheroid cultures, using low-attachment plates. These positive hit compounds can be divided into 5 categories: 1) dietary supplements (quercetin and glucosamine); 2) FDA-approved drugs (carvedilol and ciprofloxacin); 3) natural products (aloe emodin, aloin, tannic acid, chlorophyllin copper salt, azelaic acid and adipic acid); 4) flavours (citral and limonene); and 5) vitamins (nicotinamide and nicotinic acid). In addition, for the compounds quercetin, glucosamine and carvedilol, we further assessed their metabolic action, using the Seahorse to conduct metabolic flux analysis. Our results indicate that these treatments can affect glycolytic flux and suppress oxidative mitochondrial metabolism (OXPHOS). Therefore, quercetin, glucosamine and carvedilol can reprogram the metabolic phenotype of breast cancer cells. Despite having diverse chemical structures, these compounds all interfere with mitochondrial metabolism. As these compounds halt CSCs propagation, ultimately, they may have therapeutic potential.

Keywords:  FDA approved drugs; cancer stem cells; drug screening; mammospheres; natural compounds

DOI:  https://doi.org/10.18632/aging.204412
Front Oncol. 2022 ;12 1077358

Editorial: Linking cellular metabolism to hematological malignancies.

Xiujing He, Manoj Kumar Kashyap, Zhizhuang Joe Zhao, Jian Yu, Hubing Shi.



Keywords:  cellular metabolism; drug resistance; hematological malignancies; immunometabolism; metabolic reprogramming

DOI:  https://doi.org/10.3389/fonc.2022.1077358
Exp Dermatol. 2022 Nov 27.

Resistance to immune checkpoint inhibitors and the tumor microenvironment.

Shusuke Kawashima, Yosuke Togashi.

  Immune checkpoint inhibitors (ICIs) have contributed significantly to the treatment of various types of cancer, including skin cancer. However, not all patients respond; some patients do not respond at all (primary resistance), while others experience recurrence after the initial response (acquired resistance). Therefore, overcoming ICI resistance is an urgent priority. Numerous ICI resistance mechanisms have been reported. They are seemingly quite complex, varying from patient to patient. However, most involve T cell activation processes, especially in the tumor microenvironment (TME). ICIs exert their effects in the TME by reactivating suppressed T cells through inhibition of immune checkpoint molecules, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Thus, this review focuses on the resistance mechanisms based on the T cell activation process. Here, we classify the main mechanisms of ICI resistance into three categories based on: (1) antigen recognition, (2) T cell migration and infiltration, and (3) effector functions of T cells. By identifying and understanding these resistance mechanisms individually, including unknown mechanisms, we seek to contribute to the development of novel treatments to overcome ICI resistance.

Keywords:  acquired resistance; antitumor immunity; immune checkpoint inhibitors; primary resistance; tumor microenvironment

DOI:  https://doi.org/10.1111/exd.14716
Clin Cancer Res. 2022 Nov 29. pii: CCR-22-1184. [Epub ahead of print]

Associating immunotherapy and targeted therapies: facts and hopes.

Sylvain Ladoire, Cédric Rébé, François Ghiringhelli.

Immune-checkpoint inhibitors (ICIs), particularly inhibitors of the PD-1/PD-L1 axis, have modified the management of many types of cancer over the last 10 years. However, both intrinsic and acquired resistance are major clinical issues with these therapies, and only few patients are cured by ICI monotherapy. To overcome resistance, the concept of combining ICIs with other therapies is emerging and supported by many preclinical trials. Besides associations of ICIs with chemotherapy or radiotherapy, now used in clinical practice, some targeted therapies have been also reported to influence immune response of patients against cancer cells, thus showing potential synergy with ICIs. In this review, we describe the preclinical and clinical advances to date in the use of these combination strategies.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-1184
EMBO Mol Med. 2022 Dec 01. e17042

Repurposing immunosuppressants for antileukemia therapy.

Maiko Sezaki, Gang Huang.

Drug repurposing, the strategy to identify new therapeutic use for clinically approved drugs has attracted much attention in recent years. This strategy offers various advantages over traditional approaches to develop new drugs, including shorter development timelines, low cost, and reduced risk of failure. In this issue of EMBO Molecular Medicine, Liu et al show that inosine monophosphate dehydrogenase (IMPDH) inhibitors, the well-known immunosuppressants have a potent therapeutic effect on the aggressive blood cancer, acute myeloid leukemia with MLL rearrangements. Intriguingly, the antileukemia effect of IMPDH inhibitors is mediated, at least in part through the overactivation of TLR signaling and Vcam1 upregulation. The robust antileukemia effect of IMPDH inhibitors, both in vitro and in vivo, together with their mechanistic findings provides a rational basis for repurposing IMPDH inhibitors for antileukemia therapy.

DOI: https://doi.org/10.15252/emmm.202217042
Blood Cancer Discov. 2022 Dec 01. OF1-OF3

Immunosuppressive Extracellular Vesicles in CLL.

Wenqun Zhong, Wei Guo.

Cancer cells need to evade the immune system for their progression. In this issue of Blood Cancer Discovery, Gargiulo and colleagues report that in a mouse model of chronic lymphocytic leukemia, small extracellular vesicles inhibit antitumor immunity by altering CD8 T-cell transcriptome, proteome, and metabolome. See related article by Gargiulo et al., (9).

DOI: https://doi.org/10.1158/2643-3230.BCD-22-0161
J Oncol. 2022 ;2022 7727424

A Novel Prognostic Model for Acute Myeloid Leukemia Based on Gene Set Variation Analysis.

Shuai Zhang, Qianqian Wang, Haoran Xia, Hui Liu.

Acute myeloid leukemia (AML) is a malignant hematological malignancy with a poor prognosis. Risk stratification of patients with AML is mainly based on the characteristics of cytogenetics and molecular genetics; however, patients with favorable genetics may have a poor prognosis. Here, we focused on the activity changes of immunologic and hallmark gene sets in the AML population. Based on the enrichment score of gene sets by gene set variation analysis (GSVA), we identified three AML subtypes by the nonnegative matrix factorization (NMF) algorithm in the TCGA cohort. AML patients in subgroup 1 had worse overall survival (OS) than subgroups 2 and 3 (P < 0.001). The median overall survival (mOS) of subgroups 1-3 was 0.4, 2.2, and 1.7 years, respectively. Clinical characteristics, including age and FAB classification, were significantly different among each subgroup. Using the least absolute shrinkage and selection operator (LASSO) regression method, we discovered three prognostic gene sets and established the final prognostic model based on them. Patients in the high-risk group had significantly shorter OS than those in the low-risk group in the TCGA cohort (P < 0.001) with mOS of 2.2 and 0.7 years in the low- and high-risk groups, respectively. The results were further validated in the GSE146173 and GSE12417 cohorts. We further identified the key genes of prognostic gene sets using a protein-protein interaction network. In conclusion, the study established and validated a novel prognostic model for risk stratification in AML, which provides a new perspective for accurate prognosis assessment.

DOI: https://doi.org/10.1155/2022/7727424
Blood Adv. 2022 Nov 28. pii: bloodadvances.2022009010. [Epub ahead of print]

Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia.

Curtis A Lachowiez, Nicola Long, Jennifer N Saultz, Arpita Gandhi, Laura F Newell, Brandon Hayes-Lattin, Richard T Maziarz, Jessica Leonard, Daniel Bottomly, Shannon K McWeeney, Jennifer Dunlap, Richard D Press, Gabrielle Meyers, Ronan Swords, Rachel Cook, Jeffrey W Tyner, Brian J Druker, Elie Traer.

Risk stratification in acute myeloid leukemia (AML) remains principle for survival prognostication and treatment selection. The 2022 European LeukemiaNet (ELN) recommendations were recently published, with notable updates to risk group assignment. The complexity of risk stratification and comparative outcomes between the 2022 and 2017 ELN guidelines remains unknown. This comparative analysis evaluated outcomes between the 2017 and 2022 ELN criteria in patients enrolled within the multi-center Beat AML cohort. Five-hundred thirteen patients were included. Most patients had one (36% [N=183]) or two (31% [N=159]) ELN risk-defining abnormalities. In patients with two or more ELN-risk defining mutations (58% [N=297]), 44% (N=132) had mutations spanning multiple ELN risk categories. Compared to ELN 2017 criteria, the updated ELN 2022 guidelines changed assigned risk group in 15% (N=75) of patients, including 10% (N=16/160), 26% (N=29/112), and 6% (N=13/224) of ELN 2017 favorable, intermediate, and adverse-risk patients. Median OS across ELN 2022 favorable, intermediate, and adverse-risk groups was not reached (estimated 5-year OS: 53% [standard error: 0.06%]), 16.8 (95% CI: 11-48) and 9.7 (95% CI: 8.3-10.8) months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate or adverse-risk AML treated with IC (HR: 1.58 [95% CI: 1.12-2.25], p-value: 0.01) compared to ELN 2017 guidelines (HR 1.27 [95% CI: 0.88-1.85], p-value: 0.20). The updated ELN 2022 guidelines better stratify survival, namely between patients with intermediate or adverse-risk AML treated with IC. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification.

DOI: https://doi.org/10.1182/bloodadvances.2022009010
Haematologica. 2022 Dec 01. 107(12): 2810-2822

The present and future of measurable residual disease testing in acute myeloid leukemia.

James S Blachly, Roland B Walter, Christopher S Hourigan.

Considerable progress has been made in the past several years in the scientific understanding of, and available treatments for, acute myeloid leukemia (AML). Achievement of a conventional remission, evaluated cytomorphologically via small bone marrow samples, is a necessary but not sufficient step toward cure. It is increasingly appreciated that molecular or immunophenotypic methods to identify and quantify measurable residual disease (MRD) - populations of leukemia cells below the cytomorphological detection limit - provide refined information on the quality of response to treatment and prediction of the risk of AML recurrence and leukemia-related deaths. The principles and practices surrounding MRD remain incompletely determined however and the genetic and immunophenotypic heterogeneity of AML may prevent a one-sizefits- all approach. Here, we review the current approaches to MRD testing in AML, discuss strengths and limitations, highlight recent technological advances that may improve such testing, and summarize ongoing initiatives to generate the clinical evidence needed to advance the use of MRD testing in patients with AML.

DOI: https://doi.org/10.3324/haematol.2022.282034