International Journal of Molecular Sciences

Editorial

Jump to: Research, Review

3 pages, 209 KiB

Open AccessEditorial

Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders

by Amelia Maria Găman

Int. J. Mol. Sci. 2023, 24(12), 9816; https://doi.org/10.3390/ijms24129816 - 6 Jun 2023

Viewed by 1016

Abstract

Hematology represents a dynamic specialty in clinical medicine that requires solid knowledge of normal and pathological hematopoiesis, cytomorphology, pathology, immunology, genetics and molecular biology [...] Full article

(This article belongs to the Special Issue Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders)

Research

Jump to: Editorial, Review

13 pages, 2549 KiB

Open AccessArticle

Concomitant Inhibition of IRE1α/XBP1 Axis of UPR and PARP: A Promising Therapeutic Approach against c-Myc and Gammaherpesvirus-Driven B-Cell Lymphomas

by Rossella Benedetti, Andrea Arena, Maria Anele Romeo, Maria Saveria Gilardini Montani, Roberta Gonnella, Roberta Santarelli, Pankaj Trivedi and Mara Cirone

Int. J. Mol. Sci. 2022, 23(16), 9113; https://doi.org/10.3390/ijms23169113 - 14 Aug 2022

Cited by 4 | Viewed by 1877

Abstract

It is emerging that targeting the adaptive functions of Unfolded Protein Response (UPR) may represent a promising anti-cancer therapeutic approach. This is particularly relevant for B-cell lymphomas, characterized by a high level of constitutive stress due to high c-Myc expression. In this study, [...] Read more.

It is emerging that targeting the adaptive functions of Unfolded Protein Response (UPR) may represent a promising anti-cancer therapeutic approach. This is particularly relevant for B-cell lymphomas, characterized by a high level of constitutive stress due to high c-Myc expression. In this study, we found that IRE1α/XBP1 axis inhibition exerted a stronger cytotoxic effect compared to the inhibition of the other two UPR sensors, namely PERK and ATF6, in Burkitt lymphoma (BL) cells, in correlation with c-Myc downregulation. Interestingly, such an effect was more evident in Epstein-Barr virus (EBV)-negative BL cells or those cells expressing type I latency compared to type III latency BL cells. The other interesting finding of this study was that the inhibition of IRE1α/XBP1 downregulated BRCA-1 and RAD51 and potentiated the cytotoxicity of PARP inhibitor AZD2661 against BL cells and also against Primary Effusion Lymphoma (PEL), another aggressive B-cell lymphoma driven by c-Myc and associated with gammaherpesvirus infection. These results suggest that combining the inhibition of UPR sensors, particularly IRE1α/XBP1 axis, and molecules involved in DDR, such as PARP, could offer a new therapeutic opportunity for treating aggressive B-cell lymphomas such as BL and PEL. Full article

(This article belongs to the Special Issue Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders)

► Show Figures

Figure 1

18 pages, 2324 KiB

Open AccessArticle

Proteomic Investigation of the Role of Nucleostemin in Nucleophosmin-Mutated OCI-AML 3 Cell Line

by Ilaria Cela, Maria Concetta Cufaro, Maurine Fucito, Damiana Pieragostino, Paola Lanuti, Michele Sallese, Piero Del Boccio, Adele Di Matteo, Nerino Allocati, Vincenzo De Laurenzi and Luca Federici

Int. J. Mol. Sci. 2022, 23(14), 7655; https://doi.org/10.3390/ijms23147655 - 11 Jul 2022

Cited by 3 | Viewed by 1800

Abstract

Nucleostemin (NS; a product of the GNL3 gene) is a nucleolar–nucleoplasm shuttling GTPase whose levels are high in stem cells and rapidly decrease upon differentiation. NS levels are also high in several solid and hematological neoplasms, including acute myeloid leukaemia (AML). While a [...] Read more.

Nucleostemin (NS; a product of the GNL3 gene) is a nucleolar–nucleoplasm shuttling GTPase whose levels are high in stem cells and rapidly decrease upon differentiation. NS levels are also high in several solid and hematological neoplasms, including acute myeloid leukaemia (AML). While a role in telomere maintenance, response to stress stimuli and favoring DNA repair has been proposed in solid cancers, little or no information is available as to the role of nucleostemin in AML. Here, we investigate this issue via a proteomics approach. We use as a model system the OCI-AML 3 cell line harboring a heterozygous mutation at the NPM1 gene, which is the most frequent driver mutation in AML (approximately 30% of total AML cases). We show that NS is highly expressed in this cell line, and, contrary to what has previously been shown in other cancers, that its presence is dispensable for cell growth and viability. However, proteomics analysis of the OCI-AML 3 cell line before and after nucleostemin (NS) silencing showed several effects on different biological functions, as highlighted by ingenuity pathway analysis (IPA). In particular, we report an effect of down-regulating DNA repair through homologous recombination, and we confirmed a higher DNA damage rate in OCI-AML 3 cells when NS is depleted, which considerably increases upon stress induced by the topoisomerase II inhibitor etoposide. The data used are available via ProteomeXchange with the identifier PXD034012. Full article

(This article belongs to the Special Issue Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders)

► Show Figures

Figure 1

12 pages, 2067 KiB

Open AccessArticle

Biochemical, Enzymatic, and Computational Characterization of Recurrent Somatic Mutations of the Human Protein Tyrosine Phosphatase PTP1B in Primary Mediastinal B Cell Lymphoma

by Rongxing Liu, Yujie Sun, Jérémy Berthelet, Linh-Chi Bui, Ximing Xu, Mireille Viguier, Jean-Marie Dupret, Frédérique Deshayes and Fernando Rodrigues Lima

Int. J. Mol. Sci. 2022, 23(13), 7060; https://doi.org/10.3390/ijms23137060 - 24 Jun 2022

Cited by 3 | Viewed by 2028

Abstract

Human protein tyrosine phosphatase 1B (PTP1B) is a ubiquitous non-receptor tyrosine phosphatase that serves as a major negative regulator of tyrosine phosphorylation cascades of metabolic and oncogenic importance such as the insulin, epidermal growth factor receptor (EGFR), and JAK/STAT pathways. Increasing evidence point [...] Read more.

Human protein tyrosine phosphatase 1B (PTP1B) is a ubiquitous non-receptor tyrosine phosphatase that serves as a major negative regulator of tyrosine phosphorylation cascades of metabolic and oncogenic importance such as the insulin, epidermal growth factor receptor (EGFR), and JAK/STAT pathways. Increasing evidence point to a key role of PTP1B-dependent signaling in cancer. Interestingly, genetic defects in PTP1B have been found in different human malignancies. Notably, recurrent somatic mutations and splice variants of PTP1B were identified in human B cell and Hodgkin lymphomas. In this work, we analyzed the molecular and functional levels of three PTP1B mutations identified in primary mediastinal B cell lymphoma (PMBCL) patients and located in the WPD-loop (V184D), P-loop (R221G), and Q-loop (G259V). Using biochemical, enzymatic, and molecular dynamics approaches, we show that these mutations lead to PTP1B mutants with extremely low intrinsic tyrosine phosphatase activity that display alterations in overall protein stability and in the flexibility of the active site loops of the enzyme. This is in agreement with the key role of the active site loop regions, which are preorganized to interact with the substrate and to enable catalysis. Our study provides molecular and enzymatic evidence for the loss of protein tyrosine phosphatase activity of PTP1B active-site loop mutants identified in human lymphoma. Full article

(This article belongs to the Special Issue Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders)

► Show Figures

Figure 1

12 pages, 1829 KiB

Open AccessArticle

Mechanisms of Sensitivity and Resistance of Primary Effusion Lymphoma to Dimethyl Fumarate (DMF)

by Roberta Gonnella, Roberta Zarrella, Roberta Santarelli, Concetta Anna Germano, Maria Saveria Gilardini Montani and Mara Cirone

Int. J. Mol. Sci. 2022, 23(12), 6773; https://doi.org/10.3390/ijms23126773 - 17 Jun 2022

Cited by 8 | Viewed by 1738

Abstract

PEL is a rare B cell lymphoma associated with KSHV that mainly arises in immune-deficient individuals. The search for new drugs to treat this cancer is still ongoing given its aggressiveness and the poor response to chemotherapies. In this study, we found that [...] Read more.

PEL is a rare B cell lymphoma associated with KSHV that mainly arises in immune-deficient individuals. The search for new drugs to treat this cancer is still ongoing given its aggressiveness and the poor response to chemotherapies. In this study, we found that DMF, a drug known for its anti-inflammatory properties which is registered for the treatment of psoriasis and relapsing–remitting MS, could be a promising therapeutic strategy against PEL. Indeed, although some mechanisms of resistance were induced, DMF activated NRF2, reduced ROS and inhibited the phosphorylation of STAT3 and the release of the pro-inflammatory and immune suppressive cytokines IL-6 and IL-10, which are known to sustain PEL survival. Interestingly, we observed that DMF displayed a stronger cytotoxic effect against fresh PEL cells in comparison to PEL cell lines, due to the activation of ERK1/2 and autophagy in the latter cells. This finding further encourages the possibility of using DMF for the treatment of PEL. Full article

(This article belongs to the Special Issue Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

18 pages, 992 KiB

Open AccessReview

Hematopoietic Stem and Progenitor Cells (HSPCs) and Hematopoietic Microenvironment: Molecular and Bioinformatic Studies of the Zebrafish Models

by Muhammad Faisal, Mubashir Hassan, Aman Kumar, Muhammad Zubair, Muhammad Jamal, Harish Menghwar, Muhammad Saad and Andrzej Kloczkowski

Int. J. Mol. Sci. 2022, 23(13), 7285; https://doi.org/10.3390/ijms23137285 - 30 Jun 2022

Cited by 2 | Viewed by 2673

Abstract

Hematopoietic stem cells (HSCs) reside in a specialized microenvironment in a peculiar anatomic location which regulates the maintenance of stem cells and controls its functions. Recent scientific progress in experimental technologies have enabled the specific detection of epigenetic factors responsible for the maintenance [...] Read more.

Hematopoietic stem cells (HSCs) reside in a specialized microenvironment in a peculiar anatomic location which regulates the maintenance of stem cells and controls its functions. Recent scientific progress in experimental technologies have enabled the specific detection of epigenetic factors responsible for the maintenance and quiescence of the hematopoietic niche, which has improved our knowledge of regulatory mechanisms. The aberrant role of RNA-binding proteins and their impact on the disruption of stem cell biology have been reported by a number of recent studies. Despite recent modernization in hematopoietic microenvironment research avenues, our comprehension of the signaling mechanisms and interactive pathways responsible for integration of the hematopoietic niche is still limited. In the past few decades, zebrafish usage with regards to exploratory studies of the hematopoietic niche has expanded our knowledge for deeper understanding of novel cellular interactions. This review provides an update on the functional roles of different genetic and epigenetic factors and molecular signaling events at different sections of the hematopoietic microenvironment. The explorations of different molecular approaches and interventions of latest web-based tools being used are also outlined. This will help us to get more mechanistic insights and develop therapeutic options for the malignancies. Full article

(This article belongs to the Special Issue Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders)

► Show Figures

Figure 1

12 pages, 315 KiB

Open AccessReview

Antiphospholipid Antibodies and Lipids in Hematological Malignancies

by Sonia Guadalupe Barreno-Rocha, Sandra Guzmán-Silahua, Sinaí-del-Carmen Rodríguez-Dávila, Guadalupe Estela Gavilanez-Chávez, Ernesto Germán Cardona-Muñoz, Carlos Riebeling-Navarro, Benjamín Rubio-Jurado and Arnulfo Hernán Nava-Zavala

Int. J. Mol. Sci. 2022, 23(8), 4151; https://doi.org/10.3390/ijms23084151 - 8 Apr 2022

Cited by 8 | Viewed by 2747

Abstract

One of the main groups of lipids is phospholipids, which are mainly involved in forming cell membranes. Neoplastic processes such as cell replication have increased lipid synthesis, making tumor cells dependent on this synthesis to maintain their requirements. Antiphospholipid antibodies attack phospholipids in [...] Read more.

One of the main groups of lipids is phospholipids, which are mainly involved in forming cell membranes. Neoplastic processes such as cell replication have increased lipid synthesis, making tumor cells dependent on this synthesis to maintain their requirements. Antiphospholipid antibodies attack phospholipids in the cell membranes. Three main types of antiphospholipid antibodies are recognized: anti-β2 glycoprotein I (anti-β2GP-I), anticardiolipin (aCL), and lupus anticoagulant (LA). These types of antibodies have been proven to be present in hematological neoplasms, particularly in LH and NHL. This review on antiphospholipid antibodies in hematological neoplasms describes their clinical relationship as future implications at the prognostic level for survival and even treatment. Full article

(This article belongs to the Special Issue Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders)

12 pages, 794 KiB

Open AccessReview

Personalized Risk Schemes and Machine Learning to Empower Genomic Prognostication Models in Myelodysplastic Syndromes

by Hussein Awada, Carmelo Gurnari, Arda Durmaz, Hassan Awada, Simona Pagliuca and Valeria Visconte

Int. J. Mol. Sci. 2022, 23(5), 2802; https://doi.org/10.3390/ijms23052802 - 3 Mar 2022

Cited by 11 | Viewed by 2347

Abstract

Myelodysplastic syndromes (MDS) are characterized by variable clinical manifestations and outcomes. Several prognostic systems relying on clinical factors and cytogenetic abnormalities have been developed to help stratify MDS patients into different risk categories of distinct prognoses and therapeutic implications. The current abundance of [...] Read more.

Myelodysplastic syndromes (MDS) are characterized by variable clinical manifestations and outcomes. Several prognostic systems relying on clinical factors and cytogenetic abnormalities have been developed to help stratify MDS patients into different risk categories of distinct prognoses and therapeutic implications. The current abundance of molecular information poses the challenges of precisely defining patients’ molecular profiles and their incorporation in clinically established diagnostic and prognostic schemes. Perhaps the prognostic power of the current systems can be boosted by incorporating molecular features. Machine learning (ML) algorithms can be helpful in developing more precise prognostication models that integrate complex genomic interactions at a higher dimensional level. These techniques can potentially generate automated diagnostic and prognostic models and assist in advancing personalized therapies. This review highlights the current prognostication models used in MDS while shedding light on the latest achievements in ML-based research. Full article

(This article belongs to the Special Issue Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders)

► Show Figures