bims-almceb 2022-09-25 papers

Front Pharmacol. 2022 ;13 1001552

Jiyuan oridonin A induces differentiation of acute myeloid leukemia cells including leukemic stem-like cells.

Fahui Li, Congying Gao, Xueming Li, Jiangyun Wang, Yao Zhao, Yu Ke, Ying Liu, Hong-Min Liu, Zhenbo Hu, Liuya Wei, Zhe-Sheng Chen.

Acute myeloid leukemia (AML) is an aggressive form of hematological neoplasia characterized by failure of myeloid differentiation. AML is a leading cause of death from leukemia. Cytarabine chemotherapy resistance is a major source of refractory/relapsed AML. A major obstacle to the successful treatment of AML results from residual disease maintained by leukemic stem cells (LSCs), which are mostly resistant to conventional chemotherapy. Here, we determined the effect of a natural compound, Jiyuan oridonin A (JOA), on the differentiation blockade in the M2 subtype [particularly t (8;21)] of AML cells, M3 subtype of AML cells (APL cells), and leukemic stem-like cells both in vitro and in vivo. We found that JOA induced cell differentiation and suppressed the colony formation capacity in various AML cell lines (Kasumi-1, KG-1, MUTZ-8, NB4, and HL-60) without eliciting apoptosis. The mechanism of JOA-induced cell differentiation depends on the specificity of cell type. JOA mediated the differentiation of Kasumi-1 cells by activating the hematopoietic cell lineage signaling pathway, while inhibition of c-MYC was involved in the JOA-induced differentiation of NB4 cells. Moreover, JOA was identified to target leukemic stem-like cells by induced cell differentiation in vivo. These findings demonstrated that JOA could inhibit the proliferation of M2 and M3 subtypes of AML cells and leukemic stem-like cells by overcoming the differentiation blockade, which may offer a novel therapeutic strategy for AML to overcome relapse and drug resistance in patients with AML. Our findings highlight the possibility of using compounds like JOA as a promising differentiation-induced agent for the treatment of AML.

Keywords: acute myeloid leukemia; cytarabine chemotherapy resistance; differentiation blockade; leukemia stem cells; refractory/relapsed AML

DOI: https://doi.org/10.3389/fphar.2022.1001552

Front Immunol. 2022 ;13 937406

Targeting lipid metabolism reprogramming of immunocytes in response to the tumor microenvironment stressor: A potential approach for tumor therapy.

Ming Zhang, Tingju Wei, Xiaodan Zhang, Danfeng Guo.

The tumor microenvironment (TME) has become a major research focus in recent years. The TME differs from the normal extracellular environment in parameters such as nutrient supply, pH value, oxygen content, and metabolite abundance. Such changes may promote the initiation, growth, invasion, and metastasis of tumor cells, in addition to causing the malfunction of tumor-infiltrating immunocytes. As the neoplasm develops and nutrients become scarce, tumor cells transform their metabolic patterns by reprogramming glucose, lipid, and amino acid metabolism in response to various environmental stressors. Research on carcinoma metabolism reprogramming suggests that like tumor cells, immunocytes also switch their metabolic pathways, named "immunometabolism", a phenomenon that has drawn increasing attention in the academic community. In this review, we focus on the recent progress in the study of lipid metabolism reprogramming in immunocytes within the TME and highlight the potential target molecules, pathways, and genes implicated. In addition, we discuss hypoxia, one of the vital altered components of the TME that partially contribute to the initiation of abnormal lipid metabolism in immune cells. Finally, we present the current immunotherapies that orchestrate a potent antitumor immune response by mediating the lipid metabolism of immunocytes, highlight the lipid metabolism reprogramming capacity of various immunocytes in the TME, and propose promising new strategies for use in cancer therapy.

Keywords: immunocyte; immunometabolism; immunotherapy; lipid metabolism reprogramming; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2022.937406

Int J Mol Sci. 2022 Sep 11. pii: 10529. [Epub ahead of print]23(18):

Flow Cytometric Identification of Hematopoietic and Leukemic Blast Cells for Tailored Clinical Follow-Up of Acute Myeloid Leukemia.

Vera Weeda, Stefan G C Mestrum, Math P G Leers.

Acute myeloid leukemia (AML) is a myeloid malignancy that is characterized by the accumulation of leukemic blast cells, which originate from hematopoietic stem cells that have undergone leukemic transformation and/or are more mature progenitors that have gained stemness features. Currently, no consensus exists for the flow cytometric identification of normal blast cells and their leukemic counterparts by their antigenic expression profile. Differentiating between the benign cells and the malignant cells is crucial for the further deployment of immunophenotype panels for the clinical follow-up of AML patients. This review provides an overview of immunophenotypic markers that allow the identification of leukemic blast cells in the bone marrow with multiparameter flow cytometry. This technique allows the identification of hematopoietic blast cells at the level of maturing cells by their antigen expression profile. While aberrant antigen expression of a single immunophenotypic marker cell cannot be utilized in order to differentiate leukemic blast cells from normal blast cells, combinations of multiple immunophenotypic markers can enable the distinction of normal and leukemic blast cells. The identification of these markers has provided new perspectives for tailored clinical follow-up, including therapy management, diagnostics, and prognostic purposes. The immunophenotypic marker panels, however, should be developed by carefully considering the variable antigen marker expression profile of individual patients.

Keywords: CD marker expression profiles; distinction; flow cytometry; hematopoietic stem cells; leukemic stem cells

DOI: https://doi.org/10.3390/ijms231810529

Leukemia. 2022 Sep 21.

A primary hierarchically organized patient-derived model enables in depth interrogation of stemness driven by the coding and non-coding genome.

Héléna Boutzen, Seyed Ali Madani Tonekaboni, Michelle Chan-Seng-Yue, Alex Murison, Naoya Takayama, Nathan Mbong, Elvin Wagenblast, Elias Orouji, Andrea Arruda, Amanda Mitchell, Faiyaz Notta, Mark D Minden, Mathieu Lupien, Kerstin B Kaufmann, John E Dick.

Many cancers are organized as cellular hierarchies sustained by cancer stem cells (CSC), whose eradication is crucial for achieving long-term remission. Difficulties to isolate and undertake in vitro and in vivo experimental studies of rare CSC under conditions that preserve their original properties currently constitute a bottleneck for identifying molecular mechanisms involving coding and non-coding genomic regions that govern stemness. We focussed on acute myeloid leukemia (AML) as a paradigm of the CSC model and developed a patient-derived system termed OCI-AML22 that recapitulates the cellular hierarchy driven by leukemia stem cells (LSC). Through classical flow sorting and functional analyses, we established that a single phenotypic population is highly enriched for LSC. The LSC fraction can be easily isolated and serially expanded in culture or in xenografts while faithfully recapitulating functional, transcriptional and epigenetic features of primary LSCs. A novel non-coding regulatory element was identified with a new computational approach using functionally validated primary AML LSC fractions and its role in LSC stemness validated through efficient CRISPR editing using methods optimized for OCI-AML22 LSC. Collectively, OCI-AML22 constitutes a valuable resource to uncover mechanisms governing CSC driven malignancies.

DOI: https://doi.org/10.1038/s41375-022-01697-9

Biochem Biophys Res Commun. 2022 Sep 11. pii: S0006-291X(22)01282-7. [Epub ahead of print]629 152-158

De Novo design of a humanized antiCD33 antibody-oridonin conjugate for acute myeloid leukemia therapy.

Hui Feng, Yi Liu, Mengyao Zhang, Ruimin Liu, Jincheng Wang, Wenjuan Wang, Pengcheng He, Penghui Zhang, Fan Niu.

Acute myeloid leukemia (AML) is the most common blood cancer in adults. Patients' 5-year overall survival is less than 30% thus having a poor prognosis. To date, the development of novel target therapies is still necessary to ameliorate patients' survival. Antibody-drug conjugates (ADCs) represent a promising class of drugs for the treatment of AML. CD33 is highly expressed on AML cells, and the FDA-approved CD33-targeted ADC drug-gemtuzumab ozogamicin (GO) has proved the feasibility of CD33-targeted ADC drug design. In this study, we constructed a novel CD33-targeted ADC drug composed of a humanized anti-CD33 antibody and oridonin as a payload with a cleaved chemical linker. Oridonin is a natural product that has great cancer therapy potential while its poor bioavailability and targeting ability limited its clinical use. Herein, we demonstrated that antiCD33-oridonin specifically delivered oridonin in AML cells improved AML cells killing ability of oridonin. Meanwhile, it did not show any non-specific toxicity on CD33 negative cells. In summary, we developed a novel AML targeting ADC with clinical application potential, and therefore provided a new solution for the druggability improvement of oridonin.

Keywords: Acute myeloid leukemia; Antibody-drug conjugation; Cancer target therapy; Humanized antiCD33 antibody; Oridonin

DOI: https://doi.org/10.1016/j.bbrc.2022.09.032