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Molecular Mechanisms of Leukemia

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Biochemistry, Molecular and Cellular Biology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 9654

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Dr. Myunggon Ko

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Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
Interests: DNA methylation; TET proteins; hematopoietic stem cells; hematopoiesis; leukemia; cancer epigenetics; cancer therapy; drug screen; metabolic diseases; obesity; diabetes; biosensor; signaling and gene expression
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Special Issue Information

Dear Colleagues,

Hematopoietic stem cells (HSCs) in the bone marrow ensure lifelong hematopoietic homeostasis by differentiating along highly ordered differentiation pathways to create the full repertoire of blood cells. They also undergo self-renewal processes to maintain an appropriate pool of HSCs in the bone marrow. A series of genetic and epigenetic abnormalities can sometimes develop in HSPCs (hematopoietic stem and progenitors), some of which lead to the disruption of the normal self-renewal, differentiation, proliferation, and survival of HSPCs, ultimately driving the neoplastic transformation of certain hematopoietic cell populations and an accumulation of these abnormal (also called 'leukemic') cells in the bone marrow and periphery while substantially suppressing normal hematopoiesis. Changes in the cellular metabolism or altered intercellular interactions with non-hematopoietic cells within the bone marrow niche can also contribute to oncogenesis. Thus, understanding the fundamental molecular basis of normal hematopoiesis and leukemogenesis will facilitate the development of more rational and effective therapeutic interventions.

For this Special Issue, we invite original research articles or reviews that describe the molecular mechanisms of leukemia and their therapeutic applications. We will accept articles addressing how genetic or epigenetic factors modulate normal HSC self-renewal and differentiation and how their dysregulation affects the development of various types of leukemia. Furthermore, the consolidation of inputs from the HSC niche or intracellular metabolism with (epi)genetic programs to secure normal hematopoiesis and their perturbations in the pathogenesis of leukemia are also of great interest. Topics relevant to the discovery of novel genetic and epigenetic alterations, their impact on hematological oncogenesis, and advanced mechanism-based therapeutic strategies are also welcomed.

Dr. Myunggon Ko
Guest Editor

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Keywords

epigenetics
chromatin modifiers
DNA (hydroxy)methylation
histone modification
hematopoietic stem cells
self-renewal
differentiation
hematological malignancies
molecular mechanisms
epigenetic therapy

Published Papers (5 papers)

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Research

0 pages, 908 KiB

Open AccessArticle

Molecular Evaluation of the Impact of Polymorphic Variants in Apoptotic (Bcl-2/Bax) and Proinflammatory Cytokine (TNF-α/IL-8) Genes on the Susceptibility and Progression of Myeloproliferative Neoplasms: A Case-Control Biomarker Study

by Mamdoh S. Moawadh, Rashid Mir, Faris J. Tayeb, Orooba Asim and Mohammad Fahad Ullah

Curr. Issues Mol. Biol. 2023, 45(5), 3933-3952; https://doi.org/10.3390/cimb45050251 - 02 May 2023

Cited by 2 | Viewed by 1682

Abstract

The regulation of apoptosis (the programmed cell death) is dependent on the crucial involvement of BCL2 and BAX. The Bax-248G>A and Bcl-2-938 C>A polymorphic variations in the promoter sequences of the Bax and Bcl-2 gene have been recently associated with low Bax expression, progression to advanced stages, treatment resistance, and shortened overall survival rate in some hematological malignancies, including chronic myeloid leukemia (CML) and other myeloproliferative neoplasms. Chronic inflammation has been linked to various stages of carcinogenesis wherein pro-inflammatory cytokines play diverse roles in influencing cancer microenvironment leading to cell invasion and cancer progression. Cytokines such as TNF-α and IL-8 have been implicated in cancer growth in both solid and hematological malignancies with studies showing their elevated levels in patients. Genomic approaches have in recent years provided significant knowledge with the regard to the association of certain SNPs (single nucleotide polymerphisms) either in a gene or its promoter that can influence its expression, with the risk and susceptibility to human diseases including cancer. This study has investigated the consequences of promoter SNPs in apoptosis genes Bax-248G>A (rs4645878)/Bcl-2-938C>A (rs2279115) and pro-inflammatory cytokines TNF-α rs1800629 G>A/IL-8 rs4073 T>A on the risk and susceptibility towards hematological cancers. The study design has 235 individuals both male and female enrolled as subjects that had 113 cases of MPDs (myeloproliferative disorders) and 122 healthy individuals as controls. The genotyping studies were conducted through ARMS PCR (amplification-refractory mutation system PCR). The Bcl-2-938 C>A polymorphism showed up in 22% of patients in the study, while it was observed in only 10% of normal controls. This difference in genotype and allele frequency between the two groups was significant (p = 0.025). Similarly, the Bax-248G>A polymorphism was detected in 6.48% of the patients and 4.54% of the normal controls, with a significant difference in genotype and allele frequency between the groups (p = 0.048). The results suggest that the Bcl-2-938 C>A variant is linked to an elevated risk of MPDs in the codominant, dominant, and recessive inheritance models. Moreover, the study indicated allele A as risk allele which can significantly increase the risk of MPDs unlike the C allele. In case of Bax gene covariants, these were associated with an increased risk of MPDs in the codominant inheritance model and dominant inheritance model. It was found that the allele A significantly enhanced the risk of MPDs unlike the G allele. The frequencies of IL-8 rs4073 T>A in patients was found to be TT (16.39%), AT (36.88%) and AA (46.72%), compared to controls who were more likely to have frequencies of TT (39.34%), AT (37.70%) and AA (22.95%) as such, respectively. There was a notable overrepresentation of the AA genotype and GG homozygotes among patients compared to controls in TNF-α polymorphic variants, with 6.55% of patients having the AA genotype and 84% of patients being GG homozygotes, compared to 1.63% and 69%, respectively in controls. The data from the current study provide partial but important evidence that polymorphisms in apoptotic genes Bcl-2-938C>A and Bax-248G>A and pro-inflammatory cytokines IL-8 rs4073 T>A and TNF-α G>A may help predict the clinical outcomes of patients and determine the significance of such polymorphic variations in the risk of myeloproliferative diseases and their role as prognostic markers in disease management using a case-control study approach. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Leukemia)

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14 pages, 3978 KiB

Open AccessArticle

Hesperetin Induces Autophagy and Delayed Apoptosis by Modulating the AMPK/Akt/mTOR Pathway in Human Leukemia Cells In Vitro

by Ching-Yeh Lin, Ya-Hui Chen and Ying-Chih Huang

Curr. Issues Mol. Biol. 2023, 45(2), 1587-1600; https://doi.org/10.3390/cimb45020102 - 13 Feb 2023

Cited by 6 | Viewed by 1867

Abstract

Background: Hesperetin has been reported to have anticancer properties. However, the molecular mechanisms underlying its action on leukemia cells remain unclear. This in vitro study evaluated the possible mechanisms of hesperetin in leukemia cells (HL-60 and U937). Methods: Cell viability was evaluated using a cell counting kit-8 (CCK-8) assay. Apoptosis and autophagy assays were conducted through annexin V/PI staining and acidic vesicular organelle (AVO) staining. Cell cycle analysis was conducted through propidium iodide (PI) and flow cytometry. The expression of proteins related to apoptosis and autophagy, including cleaved-PARP-1, Bcl-2, Bax, LC3-I/II, Beclin-1, Atg5, p62, phospho-AMPK, AMPK, phospho-mTOR, mTOR, phospho-Akt, and Akt, in human leukemia cells were evaluated using Western blotting. Results: Hesperetin dose-dependently inhibited leukemia cell viability. However, we found a low degree of apoptosis and cell cycle arrest induced by hesperetin in U937 cells. These findings imply the presence of additional mechanisms modulating hesperetin-induced cell death. Next, we evaluated autophagy, the possible mechanism modulating cell death or survival, to clarify the underlying mechanism of hesperetin-induced cell death. Hesperetin also dose-dependently increased the ratio of LC3II/I, Atg5, and Beclin 1 and decreased p62. Moreover, 3-methyladenine (3-MA) and bafilomycin A1 (Baf-A1) inhibited hesperetin-induced autophagy. We suggest that hesperetin can protect cancer cells during the transient period and may extend survival. Furthermore, a decrease in p-mTOR and p-Akt expression and an increase in p-AMPK expression were observed. Collectively, these findings suggest that hesperetin induces autophagy by modulating the AMPK/Akt/mTOR pathway. Conclusion: Hesperetin promoted cell death in the human leukemic cell line U937 by inducing a low degree of slight apoptosis, cell cycle arrest, and autophagy. It is therefore a potential adjuvant to antileukemia therapy and may be combined with other chemotherapeutic drugs to reduce chemoresistance and side effects. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Leukemia)

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10 pages, 1829 KiB

Open AccessCommunication

“Losing the Brakes”—Suppressed Inhibitors Triggering Uncontrolled Wnt/ß-Catenin Signaling May Provide a Potential Therapeutic Target in Elderly Acute Myeloid Leukemia

by Ghaleb Elyamany, Hassan Rizwan, Ariz Akhter, Mansour S. Aljabry, Sultan Alotaibi, Mohammad A. Hameed Albalawi, Meer-Taher Shabani-Rad, Tariq Mahmood Roshan and Adnan Mansoor

Curr. Issues Mol. Biol. 2023, 45(1), 604-613; https://doi.org/10.3390/cimb45010040 - 09 Jan 2023

Viewed by 1987

Abstract

Dysregulated Wnt/β-catenin signal transduction is implicated in initiation, propagation, and poor prognosis in AML. Epigenetic inactivation is central to Wnt/β-catenin hyperactivity, and Wnt/β-catenin inhibitors are being investigated as targeted therapy. Dysregulated Wnt/β-catenin signaling has also been linked to accelerated aging. Since AML is a disease of old age (>60 yrs), we hypothesized age-related differential activity of Wnt/β-catenin signaling in AML patients. We probed Wnt/β-catenin expression in a series of AML in the elderly (>60 yrs) and compared it to a cohort of pediatric AML (<18 yrs). RNA from diagnostic bone marrow biopsies (n = 101) were evaluated for key Wnt/β-catenin molecule expression utilizing the NanoString platform. Differential expression of significance was defined as >2.5-fold difference (p < 0.01). A total of 36 pediatric AML (<18 yrs) and 36 elderly AML (>60 yrs) were identified in this cohort. Normal bone marrows (n = 10) were employed as controls. Wnt/β-catenin target genes (MYC, MYB, and RUNX1) showed upregulation, while Wnt/β-catenin inhibitors (CXXR, DKK1-4, SFRP1-4, SOST, and WIFI) were suppressed in elderly AML compared to pediatric AML and controls. Our data denote that suppressed inhibitor expression (through mutation or hypermethylation) is an additional contributing factor in Wnt/β-catenin hyperactivity in elderly AML, thus supporting Wnt/β-catenin inhibitors as potential targeted therapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Leukemia)

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11 pages, 1302 KiB

Open AccessArticle

Antileukemic Activity of hsa-miR-203a-5p by Limiting Glutathione Metabolism in Imatinib-Resistant K562 Cells

by Priyanka Singh, Radheshyam Yadav, Malkhey Verma and Ravindresh Chhabra

Curr. Issues Mol. Biol. 2022, 44(12), 6428-6438; https://doi.org/10.3390/cimb44120438 - 19 Dec 2022

Cited by 1 | Viewed by 1526

Abstract

Imatinib has been the first and most successful tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML), but many patients develop resistance to it after a satisfactory response. Glutathione (GSH) metabolism is thought to be one of the factors causing the emergence of imatinib resistance. Since hsa-miR-203a-5p was found to downregulate Bcr-Abl1 oncogene and also a link between this oncogene and GSH metabolism is reported, the present study aimed to investigate whether hsa-miR-203a-5p could overcome imatinib resistance by targeting GSH metabolism in imatinib-resistant CML cells. After the development of imatinib-resistant K562 (IR-K562) cells by gradually exposing K562 (C) cells to increasing doses of imatinib, resistant cells were transfected with hsa-miR-203a-5p (R+203). Thereafter, cell lysates from various K562 cell sets (imatinib-sensitive, imatinib-resistant, and miR-transfected imatinib-resistant K562 cells) were used for GC-MS-based metabolic profiling. L-alanine, 5-oxoproline (also known as pyroglutamic acid), L-glutamic acid, glycine, and phosphoric acid (Pi)—five metabolites from our data, matched with the enumerated 28 metabolites of the MetaboAnalyst 5.0 for the GSH metabolism. All of these metabolites were present in higher concentrations in IR-K562 cells, but intriguingly, they were all reduced in R+203 and equated to imatinib-sensitive K562 cells (C). Concludingly, the identified metabolites associated with GSH metabolism could be used as diagnostic markers. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Leukemia)

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10 pages, 1088 KiB

Open AccessArticle

RUNX1 and RUNX3 Genes Expression Level in Adult Acute Lymphoblastic Leukemia—A Case Control Study

by Dagmara Szmajda-Krygier, Adrian Krygier, Krzysztof Jamroziak, Anna Korycka-Wołowiec, Marta Żebrowska-Nawrocka and Ewa Balcerczak

Curr. Issues Mol. Biol. 2022, 44(8), 3455-3464; https://doi.org/10.3390/cimb44080238 - 01 Aug 2022

Cited by 1 | Viewed by 1803

Abstract

The genetic factors of adult acute lymphoblastic leukemia (ALL) development are only partially understood. The Runt-Related Transcription Factor (RUNX) gene family play a crucial role in hematological malignancies, serving both a tumor suppressor and promoter function. The aim of this study was the assessment of relative RUNX1 and RUNX3 genes expression level among adult ALL cases and a geographically and ethnically matched control group. The relative RUNX1 and RUNX3 genes expression level was assessed by qPCR. The investigated group comprised 60 adult patients newly diagnosed with ALL. The obtained results were compared with a group of 40 healthy individuals, as well as clinical and hematological parameters of patients, and submitted for statistical analysis. ALL patients tend to have significantly higher RUNX1 gene expression level compared with controls. This observation is also true for risk group stratification where high-risk (HR) patients presented higher levels of RUNX1. A higher RUNX1 transcript level correlates with greater leukocytosis while RUNX3 expression is reduced in Philadelphia chromosome bearers. The conducted study sustains the hypothesis that both a reduction and increase in the transcript level of RUNX family genes may be involved in leukemia pathogenesis, although their interaction is complex. In this context, overexpression of the RUNX1 gene in adult ALL cases in particular seems interesting. Obtained results should be interpreted with caution. Further analysis in this research field is needed. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Leukemia)

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